Open Access
Review

Cell-centric hypotheses of aging

Siamak Tabibzadeh1,*
1
Frontiers in Bioscience Research Institute in Aging and Cancer, 16471 Scientific Way, Irvine, CA, USA
DOI: 10.2741/4888 Volume 26 Issue 1, pp.1-49
Published: 01 October 2020
*Corresponding Author(s):  
Siamak Tabibzadeh
E-mail:  
fbs@bioscience.org
Abstract

Aging in mammals results in numerous age related pathologies such as diabetes, and Alzheimer’s disease which ultimately lead to organ failure and the demise of the organism. Numerous cell-centric hypotheses have attributed the disorders of aging to lie downstream to age dependent cellular damage to biologic signaling pathways, bio-informational molecules, telomeres, organelles, and stem cells. Here, we review these cell-centric causes of aging that range from the disposable soma theory, to somatic mutation theory, and free radical theory, to theories that ascribe aging to DNA damage and methylation (DNAaging and DNA superaging), impairment of autophagy (GarbAging), telomeric attrition, senescence, immunoscencence and inflammaging. Others view that aging is caused by MitoAging, NutrimiRaging and miRagings to exhaustion of stem cell pool. Together, the current models of aging, show the existence of damage to different cellular compartments. However, it is not yet clear which, if any, of these cellular damages represent the most proximal cause of aging.

Key words

Aging, Senescence, Immunosenescence, Hypothesis, Etiology, Review

2. Introduction

At the organismal level, aging is evident in all human beings by loss of the ability to reproduce, and damage and loss of function in organs, tissues, and cells. Many theories of aging have been offered, yet, none of these theories can explain all the cellular and organismal changes which occur with aging. Importantly, the most proximal cause of aging is currently unknown and it is not yet evident as why the epigenetic clock that accounts for the methylation status of a host of genes so precisely, can predict aging and how these methylations are induced and drive the aging process. Here, we discuss the current theories of aging.

3. Cell-centric hypotheses of aging

3.1. Disposable soma theory

Perhaps one of the earliest theories of aging is the so-called disposable soma theory. According to this theory life maintains a balance in investing its energy resources between maintaining itself by repair processes and those which are required for procreation and that aging occurs when the body invests more of its energy for somatic repair or forgoes of such an investment leading to cell death (1-2).

3.2. Somatic mutation theory

The somatic mutation theory proposes that accumulation of DNA mutations can lead to tumorigenesis and senescence (3). Consistent with this theory, studies in prokaryotes, yeast, and mammalian cells have demonstrated that oxidants are mutagens and although, there is no argument that indeed point mutations in oncogenes or tumor suppressor genes can cause cancer, there is as yet no definitive proof that such mutations in the DNA can drive all the hallmarks of aging. Yet, the anti-oxidant mechanisms are sufficiently robust and can revert back to normal, the oxidized lipids, proteins and nucleic acids (4-8).

3.3. Free radical theory and rate of living hypothesis

According to the free radical theory proposed by Denham Harman, oxidative stress is one of the most important drivers of aging. He drew parallels between the effects of aging and those that are inducible by ionizing radiation, mutagenesis, cancer, and cellular damage (9). This theory gained further traction with the identification of the enzyme, superoxide dismutase (SOD), which provided the first compelling evidence, that superoxide anions (O2−.), can be generated in vivo, and got further boost from the subsequent identification of a host of anti-oxidant defense mechanisms (7,10). This concurred with the idea, that species with a high metabolic rate, age faster and have a shorter life-span (11-12). This theory was also consistent with the “rate of living” hypothesis that senescence results from energy consumption (11,13). These two hypotheses merged when it was shown that mitochondria are the principal source of endogenous oxidants and generate O2−. and that faster respiration leads to the generation of more oxygen radicals, which drive significant damage to cell and its constituents (14-20).

In mammalian cells, reactive oxygen species (ROS) are comprised of O2−., H2O2, and .OH. ROS are generated by 5-lipoxygenase and NADPH oxidase in the mitochondria and by the mitochondrial electron transport chain (ETC) by donation of electrons by NADH or succinate to complexes I and II. Peroxisomal fatty acid metabolism generates H2O2 , and reactions by cytochrome P-450 that metabolize xenobiotic compounds, mostly of plant origin, by catalyzing their univalent oxidation or reduction can also generate oxidants. Phagocytic cells release ROS as a mixture of oxidants and free radicals, including O2−., H2O2, NO. and release hypochlorite as a “respiratory burst” in response to and in attempt of killing pathogens (3). Other sources of oxidants are enzymes that, often, in a tissue-specific manner, generate ROS under normal or pathological conditions (21).

Under normal conditions, the on·slaught damage by ROS is prevented by a host of anti-oxidant defense mechanisms that include enzymatic scavengers such as sodium dismutase (SOD), which cause the dismutation of O2−. to H2O2, as well as catalase and glutathione peroxidase (GPX), which convert H2O2 to water. Also included in these defense mechanisms are GSH reductase, and dehydroascorbate reductase which are involved in the reduction of oxidized forms of small molecular anti-oxidants as well as thioredoxin reductase which maintains protein thiols. Ascorbate (vitamin C), urate, and glutathione (GSH) act as hydrophilic radical scavengers whereas tocopherols, the major forms of vitamin E, phenolic compounds, flavonoids, carotenoids, and ubiquinol act as lipophilic radical scavengers. Glucose-6-phosphate dehydrogenase regenerates NADPH and maintains a reducing environment (3). Although diverse lines of evidence exist that support Harman’s theory, this idea can not explain all the age related pathologies, and although ROS is widely accepted to contribute to aging, substantial gaps in our knowledge still persist (22).

3.4. DamAging

According to the damage theory of aging, aging is due to the occurrence of widespread genetic changes and instability of the major informational bio-molecules, including DNA, RNA, proteins, carbohydrates and lipids (23). Such damages are considered to be major causal factors that drive the age-related alterations and diseases, and lead to decreased health-span and life-span (24-27). Random alterations in the synthesis and change in the structure of bio-molecules are thought to be the underpinning of some, but not all, of the physiological changes that we witness in aged tissues. However, the full extent of the frequency, and characteristics of changes that occur in the cellular and molecular machinery and their driving forces have not been fully realized.

Particularly vulnerable to damage are long lived molecules that exist within cells or persist for a long time in the extracellular matrix. However, it is not clear as whether such damages are causal or casual and more work is clearly needed to define the importance of such damages and whether they are unique to all cells or a subset of cells and tissues. Also, there is a need to know whether such changes cause damage or are ways that cells protect themselves from further damage. The cause of these damages have long been considered to be ROS, however, the possibility that not all damages might be related to ROS and that some damages might be due to other causes such as UV, impact of different wavelengths and environmental toxic agents can not be ruled out. Indeed, these damages might be due to the inherent and progressive failure of the damage response pathways. Based on existing models, it is clear that failure of damage repair can lead to the shortening of life-span and progeria. For example, mice with defects in DNA repair genes show premature aging that are indistinguishable from those that are displayed by wild-type aged mice (27). Similarly, a defective ubiquitin ligase/co-chaperone (Carboxyl terminus of HSP70-interacting protein) reduces life-span and causes accelerated age-related pathologies in mice (28).

3.5. DNAging and super DNAging

There are other causes for damage to biomolecules, by endogenous factors such as replication errors, oxygen free radicals, glucose and oxidative sugars and body heat and exogenous factors such as ionizing radiations and DNA damaging agents, UV rays, xenobiotics, viruses, chemicals and dietary carcinogens. Although cells have developed defense mechanisms to protect the biomolecules from these damages and have mechanisms to repair them, aging leads to the erosion of the robustness of such systems, and hence, with age, the rapidity by which such changes occur and the number of damaged molecules, increases progressively.

The DNA damage theory arose from the idea that aging might result from DNA damages that remain un-repaired and that such damages contribute to the age related pathologies. Consistent with such a theory, defects in the DNA nucleotide excision repair are associated with accelerated aging in mice while certain single nucleotide polymorphism in DNA repair genes are associated with extended life-span in humans (28-32). DNA endures damage such as single- and double-strand breaks, adducts, and crosslinks and mutations throughout life by a host of internal and environmental factors (33). Single strands of DNA are repaired via base excision repair (BER) and nucleotide excision repair (NER) and its subpathways. Double strand DNA breaks (DSB) are repaired by the non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways. DNA damage is identified by the accumulation of 8-hydroxydeoxyguanosine (oxo8dG) residues and polycyclic aromatic hydrocarbon adducts, while mutations, which may be caused by imperfect DNA replication, are specific changes that occur in specific nucleotide sequence.

It has been estimated that DNA damage occurs in mice at a rate of 25 to 115 times per minute in each cell, or about 36,000 to 160,000 per cell per day (34). Although, DNA replicates with a fairly high fidelity, the DNA polymerase in humans is subject to making errors at a rate of 1 per every 100,000 nucleotides which are then mostly corrected by various DNA enzyme repair processes (35). After the cell division is finalized, any incorrectly paired nucleotides remain as permanent mutations. Once the genes of DNA repair enzymes, themselves, are damaged, the mutation rate increases at a faster rate. Some of such enduring mutations are carcinogenic while other types of damage might change the gene expression, increase the rate of senescence or apoptosis and shorten the life-span (36-39).

Damage to the ataxia-telangiectasia mutated (ATM) kinase which detects DSBs is associated with genomic instability, DNA repair defects, immune deficiency, and premature cellular senescence that can be rescued by p53 deficiency. This disease also generates elevated ROS levels that cause further damage to the DNA. At the organismal level, the disease causes cerebellar degeneration, progeroid aging and cancer (40-41). Lending credibility that DNA mutations can be pathogenic and may shorten life-span, are a spectrum of human diseases such as Hutchinson-Gilford progeria syndrome (HGPS) that all cause premature aging. HGPS syndrome is caused by a mutation at the LMNA locus that encodes proteins of the nuclear laminae. Mutations in LMNA have also been reported in several other atypical progeroid syndromes (42). Werner syndrome (WS) that also causes progeria is due to mutations in the WRN genes (43-44). There are reports of other progeroid disorders including neonatal progeroid syndrome (NPS) or Wiedemann-Rautenstrauch syndrome that present with an “old-man” appearance since birth or childhood. These are thought to be potentially caused by DNA repair defects (45-46). Although, DNA mutations might be pathogenic, their overall contribution to age related shortening of life-span is debatable. For example, increased genomic instability has not been found to be necessary for shortened life-span in DNA repair deficient mice. Defects in the Pms2 gene, that normally corrects DNA base pair errors, increases the frequency of DNA mutations in all tissues by about 100-fold, yet, it does not shorten life-span in mice (47-48).

As compared to “averagely” aged humans, in nonagenarians (90–99 years), centenarians (100–109 years) and super-centenarians (110 years and older), the prevalence of diseases, such as cancer, cardiovascular disease, diabetes and dementia, is lower (49). This suggests that such long lived individuals possess better defense and housekeeping mechanisms and superior genetics, and chromosomal, telomeric and DNA stability that curtails the extent of such damages. Additional environmental factors such as diet, physical activity, and stress free life-style might be at work in keeping the damage to molecules at bay in these long lived humans (49).

3.6. DNAMethylAging

One of the cardinal features of aging, is the progressive and relentless life-time methylation of the DNA. The epigenetic theory of aging emerged from the observation that baseline DNA methylation levels progressively drift by aging, a process, named as “epigenetic drift”. These changes can be observed in the identical genetic backgrounds such as monozygotic twins (50). There are other locus-specific DNA methylation changes that are not dependent on gender or tissue type and reproducibly occur in all aged people. In fact, the process is so precise that the true biological aging can be deciphered from the methylation state of a handful of CpG sites (51). The DNA methylation, is deeply embedded in nature as an evolutionarily conserved process in diverse species, not only for epigenetic modification for gene silencing but also for regulation of longevity and aging (52-54). In some aging tissues, one can observe, a stochastic age-associated increase in gene expression, that is referred to as transcriptional noise (55).

Aging appears to be plastic and not fixed, to be inducible and yet reversible and longevity is known to be epigenetically controlled by specific alterations in the chromatin state. It is remarkable that epigenetic changes, not only are responsive to aging, they can act as potent drivers of the aging processes. In fact, DNA methylation patterns that are associated with gene repression are known to be dynamically changing with age and epigenome appears to act as a sensor that gauges age dependent changes due to DNA damage, environmental stresses, or inflammation and sets the cellular response to the development of metaplasia to senescence (56-58). The idea, that the DNA methylation and aging are intertwined, dates as far back as the 1987, when it was realized that aged tissues and senescent fibroblasts exhibit low levels of 5mC (59-60). This initial idea has been expanded remarkably by genome-wide analysis of methylome that clearly shows, that DNA methylation patterns, are age dependent in aging tissues and across many species (50, 61). The erosion of DNA methylation patterns involves both locus-specific hypermethylation and hypomethylation (50, 62-64). Global hypomethylation appears to signify the loss of integrity of constitutive heterochromatin, that is seen in various eukaryotes, ranging from yeasts to humans (65). The first genome-wide analysis on aging revealed, that there is an equal extent of 5hmC gain or loss, in human mesenchymal stem cells (hMSCs). These loci had distinct distribution patterns with hypo-hydroxymethylated sites being highly represented at CG-poor regions whereas the hyper-hydroxymethylated sites occurred mainly at CGIs and gene bodies (66).

Some epigenetic changes such as hypomethylation foci or methylation changes that develop at specific CGIs and may lead to transcriptional deregulation during aging are also represented in replicatively senescent cells (67-71). There are some specific epigenetic signatures that are independent from the age of the individual that correlate well with the number of replications in both fibroblasts and hMSCs (72-75). Some of these changes may play a causal role since it is known that treatment of cells with inhibitors of DNA methylation causes senescence (76). Both replicative and oncogene inducible forms of senescence have been shown to lead to an increase in the biological age as gauged by the epigenetic clock (77). However, such changes are not universal, since DNA damage induced senescent cells, do not endure such changes (77).

Foci of hypermethylation mainly occur at gene specific CG islands during aging which sometimes alter gene expression (78). Some of these hypermethylated genes also appear in age induced diseases, impaired immunocompetence in the elderly and in cancer cells (79-88). The age inducible hypomethylations occur in heterochromatic regions of the DNA. In human DNA, this includes repetitive elements and transposons which contain the majority of methylated CG dinucleotides as well as CG-poor regions which reside close to certain genes (61, 89-91 ). The so-called “open sea regions” include megabase regions that also have a low CG content (92).

Moreover, the methylation of histone which is controlled during the development, and is required for the maintenance of stem cell plasticity, is also intimately linked to aging (93-98). Histone methylation is an active process that requires the trithorax group of proteins, which trimethylate histone H3 at lysine 4 (H3K4me3), a histone mark that is required for gene activation. Indeed, whereas in-activation of a H3K4 demethylase shortens life-span, in-activation of trithorax and several H3K4 methylases has been shown to extend life-span in C. elegans (99).

The epigenomic changes start early in life as early as fertilization, continue during the development and in the pre-implantation embryos, when massive de-methylation, renders germ cells totipotent (50, 100). Even during prenatal development, the methylome is exquisitely responsive to the maternal diet (101). The Dutch Hunger Winter study showed, that embryos from mothers who experience famine, develop hypomethylation and hypermethylation of several DNA loci, and later in life, develop many health issues such as cardiovascular disease, hypertension, impaired glucose homeostasis to obesity (102-103). Even depression of the mother can alter the methylation status of the imprinted genes which, later in life, exposes the individual to diseases (104). Throughout the life of an adult, the methylation status of DNA. is also known to drift with age based on such lifestyle choices as diet and calorie intake, physical activity as well as a host of chemical, physical, biological, psychological and behavioral factors (105-106). For example, physical activity has been shown to reduce the risk of developing cancer and mortality (107-110).

Unfortunately, the epigenome which molds genomic information. loses its luster with age due to the multitude of nutritional and intracellular and extracellular, environmentally driven, stresses that deteriorate the genomic integrity. Although, this loss of genomic integrity persists, there is hope that rejuvenating interventions can be instituted that reverse the age-dependent epigenetic and gene expression drifts, as well as to normalize the biochemical changes, including protein aggregation, oxidation of informational macromolecules, and glycation (111). For example, some epigenetic changes that occur both in aging and by senescence have been shown to be reversible by reprogramming of cells into induced pluripotent stem cells (iPSCs) (112-115).

3.7. GarbAging and impairment of autophagy

Autophagy is a housekeeping and protein quality control mechanism that is required for the maintenance of cellular health by removing damaged or defective proteins and organelles by the process of macroautophagy and mitophagy. Autophagy gets activated by stress including caloric restriction, and endows cells stress resistance and longevity (116-120). It has been shown that in C. elegans, increased autophagy and expression of autophagy genes, such as bec-1, Atg-7 and Atg-12, are required for the extension of life-span (121-124). Unfortunately, the action of removal of damaged parts degrades with aging, leading to the accumulation of waste products by impaired autophagy, accumulation of defective mitochondria due to decreased mitophagy (GarbAging), with the final outcome of development of cellular senescence and age-related degenerative diseases (125-133). In mammalian liver, autophagy declines during aging, by a progressive decrease in the expression of lysosomal-associated membrane protein 2 (LAMP2) which acts as a receptor for chaperone-mediated autophagy (134). Prevention of this age induced decline in LAMP2 suppresses the accumulation of damaged proteins and improves hepatic function (135).

AMPK signaling a positive regulator for autophagy, controls autophagy through mTOR and ULK1 signaling, and leads to reduction in metabolism (136-137). AMPK regulates the formation of autophagosomes whereas mTOR inhibits autophagy (137-138). mTORC1 interacts with ULK1 complexes and regulates the metabolic balance between protein and ribosome synthesis, and the catabolic processes that require autophagy. Mammalian ULK1, an orthologue of yeast Atg1, acts as a gatekeeper for autophagosome formation by binding to phagophoric membranes and enhancement of the function of autophagic conjugation systems (139). PI3K-AKT which activates the mTOR-mediated biosynthetic processes, represses autophagic degradation. Active mTORC1 becomes associated with the ULK1/ATG13/FIP200 complex, phosphorylates ULK1 and represses its protein kinase activity. On the other hand, AMPK can induce autophagy by directly binding to the ULK1 complex and phosphorylating ULK1 and by inhibiting the activity of mTOR complex (mTORC1) by dissociating mTORC1 from the ULK1 complex, phosphorylating the Raptor, a regulatory component of mTORC1, or by phosphorylation of tuberous sclerosis protein 2 (TSC2) (137, 140-143). AMPK enhances autophagosome formation by the activation of SIRT1 signaling. SIRT1 participates in autophagy by complexing and deacetylating several autophagy proteins including Atg5, Atg7, and Atg8, that in the absence of SIRT1, are acetylated leading to the accumulation of damaged organelles in SIRT1−/− mice (144). The activation of FoxO1 and FoxO3a transcription factors also increases the expression of several autophagy-related genes leading to enhanced autophagocytosis (145-146).

3.8. MitoAging

Following the free radical theory, in the early 1980s, Jaime Miquel proposed oxyradical-mitochondrial DNA damage hypothesis. According to this hypothesis since the synthesis of the mitochondrial DNA (mtDNA) takes place at the inner mitochondrial membrane, at the vicinity of the sites that highly reactive oxygen species are formed, the mtDNA is subject to oxidative damage. In irreversibly differentiated cells, the damage entails mutation, and in-activation or loss of the mitochondrial genome leading to changes in the structural mtDNA genes for the 13 hydrophobic proteins of the respiratory chain and ATP synthase and the mitochondrial rRNAs and tRNAs. This, in turn, prevents the macromolecular turnover and organelle fission and ceases the ‘rejuvenation’ of the mitochondria (147). Thus, the fixed post-mitotic cells, deprived from the ability to regenerate their mitochondria, sustain a decrease in the number of functional organelles, develop dwindling ATP production, and curtail ATP-dependent protein synthesis and specialized physiological functions. Such an extensive decline in the cell energy reservoirs, therefore, confers to cells an aging phenotype that ultimately leads to age related degenerative diseases. In fact, mitochondrial integrity deteriorates as a function of age and defects in the mitochondrial function have been implicated in over 100 diseases. Mitochondrial DNA mutations and impaired oxidation have been shown in aging and age-related degenerative diseases such as atherosclerosis, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, amyotrophic lateral sclerosis (ALS), cardiomyopathies, and more importantly diabetes mellitus that further drives multi-organ and systemic damages (148).

Mitochondrial dysfunction can be caused by a host of causes namely, defects in ETC enzymes (Complexes I - IV), loss of of the electron carrier, coenzyme Q10, insufficient energy fuel supply or oxygen due to ischemia or anemia, or excessive membrane leakage, that results in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase. Although such defects, to some extent, can be overcome by mitochondrial biogenesis, at certain critical ATP level, cell death ensues. Defective OXPHOS may be caused by abnormal the mitochondrial function resulting from inherited or acquired mutations in the nuclear (nDNA) or mitochondrial (mDNA) (149).

Aging has also been shown to lead to the accumulation of point mutations and large-scale deletions of mtDNA, decrease in mitochondrial respiratory function, increase in mitochondrial production of ROS, which in turn, leads to oxidative damage to DNA, proteins, and lipids and enhanced apoptosis. Tissues that are highly dependent on oxygen and mitochondrial OXPHOS including cardiac, skeletal and smooth muscles, central and peripheral nervous system, kidney, and the insulin-producing pancreatic beta-cells are particularly susceptible to the mitochondrial dysfunction (149-150).

The decline in the mitochondrial function might emanate from mutations in mtDNA. Somatic mutations in mtDNA, senescence and associated age related decline in the mitochondrial function and aging at the organismal level appear to result from several causes namely, the oxidative environment within mitochondria, absence of protective histones in mtDNA, and the lack of efficient repair mechanisms for mtDNA (151-152). Consistent with this, mutations in mtDNA is associated with aging phenotypes in humans. Moreover, a mutation in the proofreading exonuclease domain of the mtDNA polymerase γ, which is associated with mtDNA mutations, leads to a decline in the mitochondrial function, premature aging and a reduced life-span in mice (153-158).

In post-mitotic tissues the levels of oxo8dG are significantly higher in mDNA than nDNA, likely due to the absence of protection shields such as histones and lack of systems that maintain the integrity of DNA replication (159). Although mitochondrial DNA can bear mutations, there is as yet no available evidence that such DNA mutations are the direct cause of cellular aging nor there is any evidence that repair of such mutations can prolong the life-span (160). Moreover, mitochondrial mutator mice that exhibit 500-fold higher mutation burden than normal mice, fail to show rapidly accelerated aging indicating that mtDNA mutations do not shorten the life-span (161). Additionally, despite age dependent accumulation of a higher level of oxo8dG in nDNA and mtDNA, mice which are heterozygous for a mutation in the mitochondrial enzyme that processes superoxide, Sod2, and exhibit life-long reduction in MnSOD activity, fail to show an accelerated aging (162).

The mammalian nuclear factor-erythroid 2-p45 derived factor 2 (Nrf2) and skinhead family member 1 (SKN-1) in C. elegans represent potent defense against oxidative stress and are known to increase life-span in model organisms (163-168). These pathways erode and become less active or get dysregulated in aging and in age-related degenerative diseases (163, 169-170). Nrf2/EpRE signaling regulates the basal and inducible expression of many antioxidant enzymes and the proteasome. The antioxidant defense enzymes responsive to Nrf2, include NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase 1 (HO-1), glutathione S-transferase (GST), glutamate cysteine ligase catalytic subunit (GCLC) and the cystine/glutamate (xCT) transporter which is involved in the adaptive up-regulation of GSH synthesis (171-175). Although, under normal conditions, Nrf2 is targeted for proteasomal degradation, by its binding to the Kelch-like ECH-associated protein (Keap1), activators of the Nrf2 pathway unleash stress-induced proteasomal activity that leads to the removal of oxidized proteins. Disruption of the basal ubiquitin-dependent degradation of Nrf2 by the 26S proteasome, leads to its nuclear accumulation and gene induction and restores redox homeostasis by increasing antioxidant/electrophilic response element-mediated (ARE/EpRE) expression of phase II and antioxidant enzymes (176). The overall activity of Nrf2 is regulated by modulation of its transcription by PI3K, P62, CBP, and BRCA1, post-translational mechanisms, and its interactions by other proteins (177). Nrf2 is negatively regulated by, Keap1, Bach1, c-Myc and a host of microRNAs. Nrf2 has been identified by siRNA screen to be the driving mechanism for the Hutchinson-Gilford progeria syndrome (HGPS), that is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein, lamin A, that leads to the nuclear sequestration of Nrf2 and impairs its transcriptional activity and consequently increases chronic oxidative stress, premature aging, and ultimately, invariably, causes death (178). An additional determinant of progeria in HGPS appears to be related to the impaired transcriptional activity of Nrf2, and the abnormal nuclear lamina-mediated mislocalization in MSCs (178). There are additional evidence that directly places Nrf2 as being involved in age related pathologies such as age induced fibrosis and for this reason, Nrf2 is a promising target for the development of novel pharmacologic or genetic therapeutic regimes (179). Nrf2 was recently found to be responsive to the apocarotenoid, bixin, an FDA-approved food additive derived from the seeds of the achiote tree (Bixa orellana). Bixin suppressed acute UV-induced photodamage and reduced epidermal hyperproliferation and oxidative DNA damage in Nrf2+/+ but not Nrf2-/- mice (180).

Preserving the mitochondrial function by a cellular stress response pathway which involves activating the mitochondrial unfolded protein response (UPRmt), leads to increased life-span in C. elegans (181). Proper the mitochondrial function appears also to be significant to the maintenance of tissue homeostasis. For example, cell proliferation appears to be intimately linked to the mitochondrial 1C metabolism-induced redox homeostasis (182). Fortunately, age-associated damage to the mitochondrial respiration can be counteracted by exercise and it is becoming clear that the maintenance of the mitochondrial function can be used to delay age related decline and as a successful avenue to extend human life-span (183).

3.9. Telomeric attrition

Telomeres are molecular clocks that count the number of cell divisions and are comprised of repetitive TTAGGG sequences at the ends of the chromosomes. In mammalian cells, telomeric ends have a a protective “t loop” a higher-order structure, comprised of a terminal 3′ single-stranded tail, the so-called “G” strand overhang, which is buried into adjacent double-stranded repetitive telomeric DNA. This loop, in turn, is stabilized by a displacement of “D” loop that is formed between the invading end of the telomere into adjacent double-stranded DNA (184). The deterioration of G strand overhangs is protected by a specialized complex that maintains their integrity, and prevents their shortening and fusion with neighboring chromosomes during replication. This complex is made of reverse transcriptase, telomerase (TERT, or hTERT in humans) and its catalytic RNA sub-unit, TERC that extends telomeres during S phase, therefore, preventing the natural shortening of telomeres (185). While telomerase is expressed in embryonic and adult male germline cells, it is absent in normal somatic cells such as fibroblasts. These cells have very low levels of telomerase activity, and following each round of cell division, telomeres shorten in each successive generations. Senescence ensues when cells ultimately end up having critically short telomeres through a process that may involve loss of the t loop structure and/or “uncapping” due to the loss of protective proteins. Such uncapped telomeres are then recognized by the cell cycle checkpoint machinery as DNA damage, which causes cell cycle arrest (186). Lack of repair of the telomeric ends leads to the erosion and shortening of telomeres following each cell division. In cells with an intact cell cycle checkpoints (G1 cell cycle block), shortening of telomeres, leads to senescence. In cells that have in-activated cell cycle checkpoints and exhibit chromosome breakage and mitotic catastrophe, and shortened telomeres and telomeric end-to-end fusions, lead to the cellular crisis (185).

The use of telomerase deficient mice has served as a model system for examining the adverse organismal and cellular consequences of lack of the telomeric maintenance. Besides mechanisms which maintain the integrity of DNA and prevent its damage, it appears that the capping function of telomeres is required to prevent the tell-tale signs of aging including activation of p53, and for prevention of stem cell depletion and decline in stem cells that cause tissue atrophy and compromised mitochondrial function, and loss of maintenance of bioenergetic homeostasis in tissues (187).

Dysfunction of the telomeric maintenance leads to various diseases such as dyskeratosis congenita that results from mutations in the gene encoding dyskerin (DKC). DKC is proposed to be a ribosomal RNA similar to the yeast protein which is involved in production of rRNA and it interacts with telomerase and stabilizes the RNA in this complex (188). On the other hand, mutation in TERT has been shown to lead to dysfunction of highly proliferative bone marrow cells resulting in aplastic anemia (189). Late-generations of TERC-deficient mice show some signs of accelerated aging (190-191).

3.10. Senescence

Hayflick and Moorhead (192) discovered that, after a limited number (50-80) of cell divisions, fibroblasts experience a permanent loss of cell proliferation and enter a state of replicative senescence. Besides replicative senescence which occurs in aging tissues, for example as a result of telomere shortening, mitogenic signals, oxidative stress or other types of damage, there are other forms of senescence. This includes DNA damage induced senescence and oncogene induced senescence which remain largely indistinguishable from replicative senescence (193-196). Senescence is intimately linked to the remodeling during embryonic development, in normal placental function as well as wound healing, and stress response (197). In healthy tissues, damaged cells undergo apoptosis and are replaced by freshly divided cells and, this division, not only removes the damaged cells, cell division, dilutes persisting damage in daughter cells. In case, that the damage is more severe, senescence is engaged to stop the cell replication, and, to prevent premalignant cells with one or two oncogenic mutations, to undergo further tumorigenic changes.

Senescent cells exhibit phenotypic and morphological changes and expansion of their cytoplasm. They also have shortened telomeres, and show an increased expression of senescence markers including senescence-associated β-galactosidase (SA-β-Gal) and of cyclin-dependent kinase inhibitors including p16 and p21 (198-200). CDKN2A locus is under epigenetic control by the gene-silencing complex, polycomb group proteins. Polycomb-repressive complex 2 (PRC2) along with its catalytic sub-unit, EZH2 trimethylates lysine 27 of histone H3 (H3K27me3). This, in young cells, in turn, recruits PRC1 which further modifies chromatin to a state that silences genes including cyclin-dependent kinase inhibitor, p16 (201). However, upon aging, the levels of EZH2 mRNA and protein levels, and the level of H3K27me3 at the CDKN2A locus dwindles, and this leads to a progressive increase in p16 expression, that causes an irreversible cell-cycle arrest and cellular senescence (202-203). JMJD3, which is inducible by replicative exhaustion, the transcription factor NFκB, or oncogenic stress can compete with EZH2 in occupying the CDKN2A, and by virtue of demethylating H3K27me3 can allow p16 expression and senescence (204-206).

p16 and p21, are well established senescence-associated markers that their expression is increased, during replicative senescence and DNA damage induced senescence (207). The activation of the p53 and Rb proteins is thought to be required for induction of senescence to prevent and suppress tumor development and, for this reason, senescence is regarded as a tumor suppressor response mechanism (208-210). Despite being a predominant tumor suppressor, once tumors occur, senescent cells provide a pro-oncogenic milieu and promote the growth of epithelial tumors (211).

Senescent cells exhibit a specific senescence secretome, the so-called Senescence-Associated Secretory Phenotype (SASP). The true microenvironmental impact of SASP and its composition varies based on the tissue and cell types which reinforces cell cycle arrest. SASP amplifies the innate immune responses, particularly those that involve the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway (cGAS-STING pathway) in response to the accumulation of cytoplasmic DNA (cytoplasmic chromatin fragments, mtDNA and cDNA)(212). SASP also leads to the immune mediated clearance of cells that have the potential to cause cancer (213). Attaining SASP, is driven by and requires, a host of cellular activity including metabolic regulators and cell survival-related transcription factors, miRNAs, RNA stability, autophagy, chromatin components, and metabolic regulators as well as DNA damage response (DDR), stress kinases, alarmin, inflammasome and inflammation. Temporally, SASP matures through an early DDR associated phase, early self amplification phase and a late phase. It is this latter phase that produces the hallmarks of SASP, namely, the anti-proliferative state, clearance of senescent cells, as well as chromatin remodeling. This stage also impacts the control of mRNA translation and intracellular trafic, and is responsible for the activation of transcription factors such as NFκB, c/EBP, release of inflammatory cytokines such as IL-6 and TNF-α and of chemokines, extracellular proteases, growth factors and bioactive lipids (214-215). p38MAPK has been described as an independent regulator of SASP phenotype (216).

Many mouse models and human diseases that cause early senescence also lead to premature aging (217). Senescent cells contribute to aging through separate mechanisms. Cellular senescence renders cells replicatively in-active and senescent cells through release of inflammatory cytokines and secretion of proteases and other factors to their environment can disrupt tissue function. Senescent cells seem to induce senescence in neighboring cells and contribute to the age related pathologies. For example, transplanting a relatively small number of senescent cells into young mice led to the spread of cellular senescence in host tissues and caused persistent physical dysfunction while introduction of fewer senescent cells to old animals reduced their life-span (218). Senescence in progenitor or stem cells is actively suppressed for example, Polycomb group repressor, Bmi1, negatively controls senescence in hematopoietic stem cells (211, 219). However, these cells are not immune to this process and their senescence occurs with normal aging, DNA damage, environmental stress, and telomeric dysfunction. Cease in stem cell replication, due to senescence, halts the normal tissue renewal and leads to tissue atrophy which is typical of aging tissues.

3.11. Immunosenescence, inflammaging and senoinflammation

Aging leads to a progressive decline in the immune responses leading to a state of dysregulated immune function (immunosenescence), and development of a low grade and sterile inflammation (inflammaging) in aging tissues as a result of an imbalance between pro- and anti-inflammatory responses to environmental pathogens including gut microbiome or endogenous, self, misplaced, or altered molecules. The prevailing view is that during aging, the immune cells fail to mount an efficient innate and adaptive immune program in response to antigens or environmental stimuli (e.g. ROS). As a consequence, the inflammatory response does not subside and becomes chronic in aging tissues (inflammaging) and provokes molecular inflammatory signals in such tissues (220-222). Inflammaging is the expansion of the network and the remodeling theory of aging (223-225).

Immunosenescence is primarily characterized by involution of the thymus, reduced reactivity of immune cells and response to vaccination or a new antigen load, auto-reactivity, autoimmunity and a lower anti-cancer and anti-microbial responses and phagocytosis (226). Immunosenescence also reduces cellular superoxide production, and naïve:memory cell ratio and leads to the expansion of mature cell clones (227). Together, the failure of autoreactive and autoimmune processes, loss of ability to remove damaged molecules and organelles and emergence of senescence, progressively fuels a chronic state of inflammation locally and systemically. These events result in a greater susceptibility of aging population to cardiovascular disease, Alzheimer's disease, and a greater rate of mortality (228-230). Thus, inflammaging and immunosenescence are considered as major targets for devising strategies to reverse age related pathologies and disorders.

The adaptive arm of immunity is more severely impacted by age than the innate immunity (231). However, only a limited number of phenotypic and functional changes have been observed in the T cell arm of the adaptive immunity (232). Moreover, cross-sectional studies of young and old population show a vastly varied distribution of immune cell types in the blood, and to some extent, a diverse aberrancy in the functional integrity of these cells (231).

Some studies have revealed biomarkers of immune aging 'immune signatures' (233). These include several parameters of the adaptive immune response, the so-called ''immune risk phenotype" (IRP) as well as assessment of NK cell markers and functions. IRP is used as a predictor of mortality in the elderly people (234). One idea that has emerged is that a significant activity of the human immune system is progressively invested heavily to control cytomegalovirus (CMV) in aging which accounts for the higher systemic levels of inflammatory mediators (233). In fact, CMV infection makes a significant contribution to the IRP (231).

The precise mechanisms that lead to inflammaging have remained elusive and are poorly characterized. However, it is believed that the inflammation may be caused by a life-time exposure to clinical and sub-clinical infections, and non-infectious antigens (235). It has been suggested that chronic activation of immune cells, leads to remodeling of the immune system which favors induction of a chronic state of inflammation leading to tissue injury and pathology (235). Alternatively, the so-called “cellular exhaustion” as a result of reduced thymic output and T cell repertoire and concomitant increased oligoclonal expansion of memory and effector-memory cells contributes to inflammaging (236). Together, the inability to forcefully respond to novel pathogens as well as an increase in functionally distinct T-cell populations significantly prolongs infection, induces a pro-inflammatory phenotype and evokes a robust cytokine production in elderly population (237). The importance of the tissue injury that results from the chronic accumulation of polymorphonuclear neutrophils (PMN), their release of ROS and oxidative damage also appear to play a significant role in inflammaging (238).

The molecular inflammation hypothesis of the aging considers that the derangement in redox is the major factor for upregulation of NFκB, IL-1beta, IL-6, TNFα, cyclooxygenase-2, adhesion molecules, and inducible NO synthase and increased risk for age-related inflammation (239). The term “senoinflammation” is applied to the emergence of pro-inflammatory senescence-associated secretome, inflammasome, ER stress, Toll-like receptors (TLR)s, and microRNAs in aging tissues. The activators of seno-inflammation, the redox-sensitive core transcription factor NFκB, polarized macrophages, and a host of miRNAs are metabolically linked to the pro-inflammatory processes such as ER stress and autophagic activity (240). Single cell transcriptomics in aging rats showed that aging leads to the infiltration of aged tissues by neutrophils and by the macrophages that attain a pro-inflammatory (M1) state (241). M1/M2 macrophage activation occurs in a wide number of age related diseases including obesity, atherosclerosis or pulmonary fibrosis (242). However, CR blocks such responses and promotes the anti-inflammatory M2 profile in macrophages (241).

A complex array of inter-related genetic, environmental and age-related factors appear to account for the vulnerability or resilience of people to inflammaging. These factors include, but are not limited to, the responsiveness of promoter regions of cytokines, cytokine receptors and antagonists, age-related decreases in autophagy and obesity (243). The inflammatory signals include damaged molecules (self garbage), an array of nDNA, mtDNA, and miRNA that are encompassed in extracellular vesicles that freely enter the bloodstream. Continuous activation of macrophages by these damaged molecules (GarbAging) ultimately exhausts their ability to clear them and that surface receptors of macrophages sense the mis-placed self molecules and activate the inflammaging by activation of inflammasome (133). NLRP3 inflammasome is comprised of an intracellular multi-protein complex that recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMP), which when activated, it leads to the release of IL-1β as well as IL-18 (244). The NLRP3 inflammasome is activated in age related disorders including obesity, insulin resistance, and inflammation (245-246). Another factor involved in aging is the failure to remove the host of cell debris and damaged organelles, by autophagy or mitophagy due to a progressive failure of proteasome.

Aging is associated with the release of a large number of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IL-22, IL-23, TNF-α, and IFN-γ in aged tissues that likely contribute to aging pathologies (227, 247-249). The inflammatory response is initiated by inflammasome, cytosolic multi-protein oligomers that are required and activate the inflammatory responses of cells of the innate immune system, and is significant in protection against pathogens and in recovery from injury. Inflammasome leads to the proteolytic cleavage, maturation and release of pro-inflammatory cytokines. The inflammasome can lead to the oxidative stress that occurs with aging and to a form of programmed cell death related to the inflammatory response, known as pyroptosis (250). The inflammasome proteins including NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are shown to be elevated in the cytosol of cortical lysates in aged mice (251). The nucleotide metabolites have been shown to activate the NLRC4 inflammasome in old individuals (252).

The canonical Nlrp3 inflammasome controls a systemic low grade age-related ‘sterile’ inflammation in both periphery and brain that appears to be independent from the non-canonical caspase-11 inflammasome. Nlrp3 knockout has been shown to protect mice from age-related increases in the innate immune activation, alterations in CNS transcriptome and astrogliosis. Thus, Nlrp3 appears to link the systemic low grade inflammation to a significant functional decline that is observed in aging.

Progressive decrease in subcutaneous tissues and loss of muscle mass (sarcopenia) during aging are associated with sequential increase in fat that is deposited in viscera, or infiltrates major organs including liver, bone and muscle. These fat depots are not inert and they act as an endocrine or paracrine organ by release of hundreds of adipokines, and pro-inflammatory peptides (253-256). For example, leptin, which has a primary role in energy homeostasis, leads to the release of a number of proinflammatory cytokines, including TNF and IL-6, stimulates differentiation of monocytes into macrophages, and activates NK-lymphocytes (256). On the other hand, declining levels of adrenal steroid dehydroepiandrosterone (DHEA) and anti-inflammaging strategies such as higher levels of cortisol, as a result of upregulation of the hypothalamic-pituitary axis in response to inflammaging, appear to exert an adverse effect in aging population (243). Long lived individuals and centenarians have developed anti-inflammaging strategies that oppose the adverse consequences of sub-clinical tissue inflammation (227).

An arsenal of different approaches including cytokine therapy, hormonal replacement, anti-oxidant supplementation, and caloric restriction have all been proposed for attenuating or potentially reversing immunosenescence (257).

3.12. Stem cell exhaustion

Other than long lived cells such as neurons and myofibers, all the cells in the body are subject to wear and tear and must be replaced periodically to maintain the normal function and physiology of tissues and organs (258-260). This task is assigned to the adult stem cells, such as hematopoietic stem cells (HSCs), intestinal stem cells (ISCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), muscle stem cells (MuSCs), hair follicle stem cells (HFSCs) and germinal stem cells (GSCs) and satellite cells that maintain tissue regeneration and homeostasis (261-266). Therefore, the decline in stem cell number or function, the so-called stem cell exhaustion, is an important driver of aging (267). For example, consistent with a general decline in cell-cycle activity, HSCs show reduced cell division in aged mice (268). Also, age-associated decline in the differentiation of HSC populations generates fewer adaptive immune cells and leads to anemia in aged organisms (269). Defects in cell-cycle by DNA damage or chromosome disorganization also significantly and adversely reduce the functional activity of HSCs, and decreases blood production in aged organisms (270). Like other aged cells, aging population of stem cells with declined function, show evidence of age related DNA damage and exhibit an increased levels of p16INK4a (271-272). Accelerated proliferation in stem cells, for example, by p21 prematurely exhausts the population of HSCs and NSCs (273-274).

In recent years, many causes of stem cell exhaustion have been defined. Stem cells appear to be under the control of the same signaling pathways that are disturbed by aging and those that can manipulate aging such as nutrient sensing pathways, telomere attrition, oxidative and mitochondrial damage, and genetic and epigenetic modulators of aging (275-281). One of the critical cause of stem cell exhaustion is aberrant nutrient signaling since it is known that Calorie Restriction (CR), Dietary Restriction (DR) and pharmacological manipulations of metabolic pathways that slow the metabolism and modify the epigenetic landscape can extend life-span whereas enhanced anabolic signaling and obesity have a reverse consequence (282-285). It has been shown that DR promotes the proliferation of ISCs through the nutrient signaling, mTORC1 and Sirtuin 1 (SIRT1), whereas rapamycin that inhibits mTOR prevents the exhaustion of these stem cells (286).

Other types of stem cell exhaustion have been attributed to the impaired autophagy that normally preserves quiescence and stemness and prevents stem cell senescence (287). For example, impaired autophagy leads to an imbalance in proteostasis, causes mitochondrial dysfunction, ramps up oxidative stress and causes satellite cells to senesce (288). SIRT1 which also regulates autophagy, is required for activation of MuSC that normally sustain a quiescent state (289). Conversely, the transcription factor, FOXO3, plays an important role in maintaining the quiescent state of NSCs and MuSCs, and is known to induce autophagy in HSCs under conditions of starvation by regulating genes involved in autophagy (290-294). Also, mTOR signaling which activates quiescent MuSCs and HSCs in nutrient-rich environments, is known to suppress autophagy and to limit life-span (295-297). Thus, it appears that autophagy is involved in stem cell aging by coordinately impacting their metabolism and epigenetic changes.

Stem cells express telomerase, yet, the telomeres of HSCs, NSCs, HFSCs and GSCs have been shown to shorten with aging (298-299). However, the real impact of telomere shortening in stem cells is not yet clear since mice that lack telomerase RNA component, TERC, fail to show any specific phenotype for three generations, and only in the fourth generation, they start to exhibit aberrant HSC lineage potential and stem cell exhaustion emerges only in their sixth generation (300-301).

The metabolome has an intimate link to epigenetic modifiers since it is, by now, clear that the metabolites derived from cellular metabolism can act as co-factors of epigenetic enzymes that induce chromatin modifications such as methylation or demethylation of histones or DNA or acetylation and deacetylation of histones (285). Thus, metabolism is one of most influential driving force that shapes the epigenetic landscape and provides the opportunity to use such co-factors as potential targets to reverse the aging epigenome including those in stem cells, to preserve their function and to prevent their senescence. It is also becoming increasingly clear that health-span and life-span and maintenance of stem cell populations are subject to modulation by regulators of nutrient sensing and cellular metabolism such as mTOR and insulin-FOXO pathways as well as by regulation of enzymes such as sirtuins, that utilize metabolites such as NAD+, which is known to be capable in changing the global levels of histone acetylation (302-304). For example, NAD+ has been shown to be involved in the activation of murine MuSC by switching, from fatty acid oxidation in quiescent cells, to glycolysis via an increase in the overall acetylation levels of H4K16 (305). Knockdown of phosphoserine aminotransferase 1 (Psat1) affects ESC differentiation by changing the levels of the metabolite, α-ketoglutarate (306). Besides NAD+ and α-ketoglutarate, another metabolite involved in murine threonine metabolism, S-adenosyl methionine (SAM), induces age-related alterations of H3K4 methylation by acting as a co-factor for histone methyltransferases (307-308).

The epigenetic fate of MuSCs appears to be under the regulation of Sirt1 that senses the cellular energetic state via NAD+ (266). Moreover, in-activation of Sirt1 leads to the abnormal expression of genes involved in amino acid metabolism, and a coordinate abnormal expansion of oligodendrocyte progenitors in mouse NSCs (309). On the other hand, Sirt6 deficiency, has been shown to impair the transcription of target genes of the anti-oxidant Nrf2 pathway, which is vital to the metabolic systems for modulating redox homeostasis. These transcriptions can be halted by the H3K56 acetylation, which in turn, appears to be sufficient to derail the normal redox homeostasis, leading to the senescence of human MSCs (310). Among the sirtuin members, Sirt7 is downregulated with age. This sirtuin, which modulates UPRmt in response to the mitochondrial stresses, has been shown to be required for the maintenance of homeostasis of HSCs, partially by acting as a repressor of genomic targets of Nrf1 (311).

Age related pathologies such as Parkinson's disease (PD) lead to the exhaustion of NSCs, defects in neuronal differentiation and DNA repair (312 ). The induction of stem cell rejuvenation in vivo in age associated phenotypes has lent support for the concept that stem cell exhaustion is one of the hallmarks of aging (313-315). Thus, understanding the mechanisms that drive stem cell aging and decline in their ability to regenerate tissues is of great significance to remedy the age related pathologies and tissue atrophy which is one of the cardinal features of aged tissues. In vivo stem cell rejuvenation, has been offered as a significant recipe and as one of the anti-aging intervention at least for the reversal of some of the aging phenotypes (313).

Stem cell exhaustion is also frequently observed in genetic diseases that shorten life-span and increase the mortality in individuals with Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome (WS), and Fanconi anemia (FA) (316-319). Premature aging in WRN has been attributed to the exhaustion of MSCs as a result of genome instability due to the deficiency of the DNA helicase and WRN protein (315, 320-321).

3.13. NutrimiRAging

The nutrient sensing, which is regulated by multiple pathways including insulin/IGF-1 (IIS), PI3K, AKT, mTOR, AMPK, Sirtuin and PGC1α, appears to be deregulated in aging, providing a strong link between diet and aging. The fact that life can be extended by alterations of the diet and that calorie, diet and protein restrictions can extend the life-span, in diverse organisms, have strengthened the notion that aging results from insults mediated by the total calorie intake and the composition of the diet. The idea, that the metabolic rate and aging are intimately intertwined, emerged from observations, that reducing the metabolism by lowering the ambient temperature in worms and flies or reducing nutrients by limiting glucose in the culture media of yeasts, leads to life-extension (322). These and other similar observations placed mitochondria as well as nutrition at the forefront of forces that drive aging.

Glucose, amino acids and fatty acids are the main fuel sources that drive energy production by conversion of ADP to ATP and for fulfilling the cellular need for NAD+. Each of the fuels require specific enzymatic and metabolic pathways and drive specific expression and utilization of surface receptors and nuclear transcription of members of the metabolic machinery. Cells have developed a complex array of signaling systems that respond to the fuel needs and sense the requirement of cells for gene expression, protein synthesis, growth, repairs and other functions. The nutritional sensing pathways that respond to dietary nutrients, degrade with age and lose their effectiveness, hence, leading to the idea that de-regulated nutritional sensing leads to loss of healthy aging and age related pathologies. The dietary restriction of nutrients, has been shown to extend life-span in C. elegans to Drosophila and mammals, leaving no doubt that life-span can be modified by reducing the total calorie intake and by restricting food and proteins particularly, sulfur containing amino acids. It is by now considered that the trans-sulfuration pathways including hydorgen sulfide (H2S) tie the nutrition and nutrient-sensitive signaling to a healthy life-span (323-325).

3.14. miRagings

miRagings are the RNA sequences that impact aging through nutrient sensing pathways, as well as those that their expression changes with diet and aging. Also included are those that inhibit target genes linked to cell proliferation, apoptosis or metabolism, or play a role in the epigenetic regulation of gene expression or biological processes that are linked to aging (326-329). These RNAs include microRNAs (miRNA) and non-coding RNAs of about 22 nucleotides that reside within intra- or inter-regions of protein coding genes. Some of these RNAs are released into plasma and body fluids such as urine and cerebrospinal fluid, that due to the necessity of being protected from RNAses and degradation, are usually associated with lipoproteins or protein complexes or are present within exosomes (330).

Circulating miRNAs are potential biomarkers of health and might be useful to discriminate healthy from abnormal aging. The circulating levels of these group of miRNAs also changes with nutritional status and by age, potentially, by upregulation of p53 which can impact the Drosha complex and miRNA maturation (331-332). Expression profile of microRNAs in centenarians were more similar to those of young adults than those of octogenarians (80-89 years of age) suggesting that their expression level might be useful in predicting longevity (332). Expression of miRNAs namely, let-7 family, miR-33, miR-103, miR-107 and miR-29 which modulate insulin signaling pathway also changes by age related pathologies including type 2 diabetes (331-338). There are a class of miRNAs that are regulated by the pathways that are known to be involved in aging. Among these, miR-124a, which is involved in glucose-induced insulin secretion, is under the direct modulation of AKT3 and FOXA2 and, potentially, SIRT1. The IGF1/PI3K/AKT/MTOR pathway is regulated by let-7 expression, a microRNA that targets multiple components of the IGF1 pathway and mTOR (339). Other miRNAs such as miR-208a and miR-133a are overexpressed after an acute myocardial infarction, and circulating miR-423-5p is upregulated in heart failure (340-342). The expression of miR-146, miR-155 and miR-21 is changed by inflammation, a typical feature of aging and miR-155 and miR- are upregulated in B-cells of elderly (343-344). Despite the wealth of knowledge that aging changes the expression of many of known miRNAs, their direct impact and relevance in aging and age related disorders is still poorly understood (267).

3.15. Other theories of aging

There are a large number of theories that have attempted to explain aging. However, many theories have failed to adequately address all aspects of aging. This includes programmed theory, that argues that aging follows a pre-determined timetable, and others that posit that aging is due to a life-time accumulation of environmentally induced damage (345). The programmed theories are sub-divided into programmed longevity due to alteration of gene expression and senescence, endocrine or reproductive-cell cycle theories that maintain that aging is hormonally regulated, and immunological theory that describes aging to be attributable to immunological decline. The damage theory is sub-divided into wear and tear theory, rate of living theory, cross linking theory, and free radical theory (9, 346-349). Dis-engagement and activity theories indicate that aging might be impacted by social engagement and physical activity. In contra-distinction, according to the quasi-programmed theory, aging is not programmed, but rather is a consequence of genetic programs that determine, developmental growth, early in life (350-352).

There are two highly repetitive regions in the genome, namely the telomeres and rRNA genes (rDNA). The finding that stability within rDNA regulates life-span led to the rDNA theory of aging. Recent studies have confirmed that the rDNA copy andthe stability of the repeats play a critical role in the control of aging and cellular senescence (353). Recently, it was shown that tissue-specific methylation of rDNA promoter strongly correlates with a lower expression of rRNA (354). We showed that replicative senescence leads to reduced levels of 18S, 5.8S and 28S rRNA, in replicative senescence and that promoter region of rRNA is hypermethylated, features that do not exist in DNA damage induced senescence (355).

Moreover, Cairns proposed the so-called “immortal DNA strand hypothesis” that hypothesizes that there are mechanisms that maintain the genome stability in stem cells that undergo rapid cell divisions to maintain tissue homeostasis (356). The stem cells divide asymmetrically giving rise to a new daughter cell that harbors the old organelles and mis-folded proteins and a younger self-renewed stem cell that retains the healthy parts of the original cell. However, the asymmetric segregation of DNA remained controversial and some suggested that random segregation occur in stem cells. However, there are some evidence that lend support for this theory in tissues such as fly male germline cells and in mouse hematopoietic system, mammary tissue, intestinal epithelium, skeletal muscle, and hair follicle (357-363).

4. Conclusions

Aging occurs in a progressive and sustained manner in all humans. Aging leads to a significant morbidity and mortality towards the end of life and exerts a significant burden to the society and to the world’s economy. Therefore, prevention or reversal of aging, is of paramount importance to all humans and eradication of aging, would undoubtedly lead to more prosperous societies across the globe. Throughout the past few decades, numerous hypotheses have been offered that all show that aging is associated with gradual and progressive decline in cell functions that arise as a result of damage to cellular compartments, organelles and bio-informational molecules. However, these cell-centric hypotheses fail to account for all the hallmarks of aging and currently, the most proximal cause of the cellular damage have remained elusive (1, 185, 236, 267, 277, 315, 321).

Abbreviations: Deoxyribonucleic acid (DNA), Mitochondria DNA (mDNA), Nuclear DNA (nDNA), Ribonucleic acid (RNA), Ribosomal RNA (rRNA), Adenosine triphosphate (ATP), Electron transport chain (ETC), Superoxide dismutase (SOD), Reactive oxygen species (ROS), Heat shock protein (HSP), Base excision repair (BER), Nucleotide excision repair (NER), Double strand DNA breaks (DSB), Ultraviolet (UV), Hutchinson-Gilford progeria syndrome (HGPS), Ataxia-telangiectasia mutated (ATM), Werner syndrome (WS), Fanconi anemia (FA), Neonatal progeroid syndrome (NPS), Human mesenchymal stem cells (hMSCs), Induced pluripotent stem cells (iPSCs), mTOR complex (mTORC1), Tuberous sclerosis protein (TSC), Amyotrophic lateral sclerosis (ALS), Oxidative phosphorylation (OXPHOS), Mn superoxide dismutase (MnSOD), Non-homologous end-joining (NHEJ), Homologous recombination (HR), Mammalian nuclear factor-erythroid 2-p45 derived factor 2 (Nrf2), Skinhead family member 1 (SKN-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), Heme oxygenase 1 (HO-1), Glutathione S-transferase (GST), Glutamate cysteine ligase catalytic subunit (GCLC), Cystine/glutamate (xCT) Transporter, antioxidant/electrophilic response element-mediated (ARE/EpRE), Unfolded protein response (UPRmt), Reverse transcriptase, Telomerase (TERT), Dyskerin (DKC), Senescence-Associated Secretory Phenotype (SASP), Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), DNA damage response (DDR), Tumor necrossis factor (TNF), Interleukin (IL), Cytomegalovirus (CMV), Immune risk phenotype (IRP), Polymorphonuclear neutrophils (PMN), Endoplasmic reticulum (ER), Toll-like receptors (TLR), Damage associated molecular patterns (DAMP), Caspase recruitment domain (ASC), Dehydroepiandrosterone (DHEA), Hematopoietic stem cells (HSCs), Intestinal stem cells (ISCs), Mesenchymal stem cells (MSCs), Neural stem cells (NSCs), Muscle stem cells (MuSCs), Hair follicle stem cells (HFSCs), Germinal stem cells (GSCs), Sirtuin (SIRT), Phosphoserine aminotransferase 1 (Psat1), Nicotinamide adenine dinucleotide (NAD), Parkinson's disease (PD), Insulin/IGF-1 (IIS), Hydorgen sulfide (H2S), Dietary restriction (DR), Calorie restriction (CR), Pathogen-associated molecular patterns (PAMPs), Damage associated molecular patterns (DAMP), S-adenosyl methionine (SAM)
References

    1. Shay JW, Wright WE. Hallmarks of telomeres in ageing research. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. Jan 211(2):114-23. (2007)

    2. Kirkwood TB. Genetic basis of limited cell proliferation. Mutation Research/DNAging. Mar 1 256(2-6):323-8. (1991)

    3. Beckman KB, Ames BN. The free radical theory of aging matures. Physiological reviews. Apr 1. 78, 547-581 (1998)

    4. Bohr VA, Anson RM. DNA damage, mutation and fine structure DNA repair in aging. Mutation Research/DNAging. Oct 1 338(1-6):25-34. (1995)

    5. Croteau DL, Bohr VA. Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. Journal of Biological Chemistry. Oct 10 272(41):25409-12. (1997)

    6. Cunningham, R. P. DNA repair: caretakers of the genome? Curr. Biol. 7: R576-R579. (1997)

    7. Tchou J, Kasai H, Shibutani S, Chung MH, Laval J, Grollman AP, Nishimura S. 8-Oxoguanine (8-hydroxyguanine) DNA glycosylase and its substrate specificity. Proceedings of the National Academy of Sciences. Jun 1 88(11):4690-4. (1991)

    8. Pacifici RE, Kono Y, Davies KJ. Hydrophobicity as the signal for selective degradation of hydroxyl radical-modified hemoglobin by the multicatalytic proteinase complex, proteasome. Journal of Biological Chemistry. Jul 25 268(21):15405-11. (1993)

    9. Harman D. Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. Journal of gerontology. Oct 1 23(4):476-82. (1968)

    10. Packer L, Fuehr K. Low oxygen concentration extends the lifespan of cultured human diploid cells. nature. Jun 267(5610):423-5. (1977)

    11. Rubner, M. Das problem der Lebensdauer und seine Beziehungen zu Wachstum und Ernèhrung. Munich: Oldenburg (1908)

    12. Ohal, R. S. Metabolic rate and life span. In: Cellular Aging: Concepts and Mechanisms, edited by R. Witler. Basel: Karger, p. 25-40. (1976)

    13. Earl, R. The Rate of Living. London: Univ. of London Press (1928)

    14. Johnson F, Giulivi C. Superoxide dismutases and their impact upon human health. Molecular aspects of medicine. Aug 1 26(4-5):340-52. (2005)

    15. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiological reviews. Jul 59(3):527-605. (1979)

    16. Giannopolitis CN, Ries SK. Superoxide dismutases: I. Occurrence in higher plants. Plant physiology. Feb 1 59(2):309-14. (1977)

    17. Davies KJ. Oxidative stress: the paradox of aerobic life. InBiochemical Society Symposia 61, 1-31). Portland Press Limited. (1995)

    18. Fridovich I. Superoxide radical and superoxide dismutases. InOxygen and living processes 250-272. Springer, New York, NY. (1981)

    19. Halliwell B. Free radicals, reactive oxygen species and human disease: a critical evaluation with special reference to atherosclerosis. British journal of experimental pathology. Dec 70(6):737. (1989)

    20. Yu BP. Cellular defenses against damage from reactive oxygen species. Physiological reviews. Jan 1 74(1):139-62.(1994)

    21. Halliwell, B. H., and J. M. C. GutteridgE. Free Radicals in Biology and Medicine. Oxford, UK: Oxford Univ. Press. (1989)

    22. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. cell. Feb 25 120(4):483-95. (2005)

    23. Campisi J, Vijg J. Does damage to DNA and other macromolecules play a role in aging? If so, how? Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences. Feb 1 64(2):175-8. (2009)

    24. Vijg JA, Busuttil RA, Bahar R, Dollé ME. Aging and genome maintenance. Annals of the New York Academy of Sciences. Dec 1055(1):35-47. (2005)

    25. Herbst A, Pak JW, McKenzie D, Bua E, Bassiouni M, Aiken JM. Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. Mar 1 62(3):235-45. (2007)

    26. Garinis GA, Van der Horst GT, Vijg J, Hoeijmakers JH. DNA damage and ageing: new-age ideas for an age-old problem. Nature cell biology. Nov 10(11):1241-7. (2008)

    27. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. Does oxidative damage to DNA increase with age? Proceedings of the National Academy of Sciences. Aug 28 98(18):10469-74. (2001)

    28. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC. Extension of murine life span by overexpression of catalase targeted to mitochondria. science. Jun 24 308(5730):1909-11. (2005)

    29. Hoeijmakers JH. "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475-85. (2009)

    30. Cho M, Suh Y. "Genome maintenance and human longevity". Curr. Opin. Genet. Dev. 26: 105-15. (2014)

    31. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. Feb 25 120(4):497-512. (2005)

    32. Cao J, Venton L, Sakata T, Halloran BP. Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice. Journal of Bone and Mineral Research. Feb 18(2):270-7. (2003)

    33. Vijg J. Somatic mutations and aging: a re-evaluation. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. Jan 17 447(1):117-35. (2000)

    34. Vilenchik MM, Knudson AG. Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates. Proceedings of the National Academy of Sciences. May 9 97(10):5381-6. (2000)

    35. Pray L. DNA replication and causes of mutation. Nature education. Jan 1 1(1):214. (2008)

    36. Best BP. Nuclear DNA damage as a direct cause of aging. Rejuvenation research. 2009 Jun 1 12(3):199-208.

    37. Freitas AA, De Magalhães JP. A review and appraisal of the DNA damage theory of ageing. Mutation Research/Reviews in Mutation Research. Jul 1 728(1-2):12-22. (2011)

    38. Burhans WC, Weinberger M. DNA replication stress, genome instability and aging. Nucleic acids research. Dec 1 35(22):7545-56. (2007)

    39. Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood. Feb 1 131(5):488-95. (2018)

    40. Bassing CH, Alt FW. The cellular response to general and programmed DNA double strand breaks. DNA repair. Aug 1 3(8-9):781-96. (2004)

    41. Shiloh Y, Kastan MB. ATM: genome stability, neuronal development, and cancer cross paths. Advances in cancer research. Jan 1 83:210-54. (2001)

    42. Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). Journal of human genetics. May 48(5):271-4. (2003)

    43. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Lévy N. Lamin a truncation in Hutchinson-Gilford progeria. Science. Apr 17. (2003)

    44. Heyn H, Moran S, Esteller M. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome. Epigenetics. Jan 1 8(1):28-33. (2013)

    45. Arboleda G, Ramírez N, Arboleda H. The neonatal progeroid syndrome (Wiedemann-Rautenstrauch): A model for the study of human aging?. Experimental gerontology. Oct 1 42(10):939-43. (2007)

    46. Hou JW. Natural course of neonatal progeroid syndrome. Pediatrics & Neonatology. Jun 1 50(3):102-9. (2009)

    47. Dollé ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J. Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. Apr 11 596(1-2):22-35. (2006)

    48. Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM. Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proceedings of the National Academy of Sciences. Apr 1 94(7):3122-7. (1997)

    49. Franzke B, Neubauer O, Wagner KH. Super DNAging-new insights into DNA integrity, genome stability and telomeres in the oldest old. Mutation Research/Reviews in Mutation Research. Oct 1 766:48-57. (2015)

    50. Ciccarone F, Tagliatesta S, Caiafa P, Zampieri M. DNA methylation dynamics in aging: how far are we from understanding the mechanisms?. Mechanisms of ageing and development. Sep 1 174:3-17. (2018)

    51. Horvath S. DNA methylation age of human tissues and cell types. Genome biology. Oct 1 14(10):3156. (2013)

    52. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. Sep 22 289(5487):2126-8. (2000)

    53. Chen D, Steele AD, Lindquist S, Guarente L. Increase in activity during calorie restriction requires Sirt1. Science. Dec 9 310(5754):1641. (2005)

    54. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. Jul 466(7304):383-7. (2010)

    55. Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature. Jun 441(7096):1011-4. (2006)

    56. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa JP. Widespread and tissue specific age-related DNA methylation changes in mice. Genome research. Mar 1 20(3):332-40. (2010)

    57. Mugatroyd C, Wu Y, Bockmühl Y, Spengler D. The Janus face of DNA methylation in aging. Aging (Albany NY). Feb 2(2):107. (2010)

    58. Martin GM. Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of aging. Aging Cell. Dec 8(6):761-4. (2009)

    59. Wilson VL, Jones PA. DNA methylation decreases in aging but not in immortal cells. Science. Jun 3 220(4601):1055-7. (1983)

    60. Wilson VL, Smith RA, Ma SH, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. Journal of Biological Chemistry. Jul 25 262(21):9948-51. (1987)

    61. Day K, Waite LL, Thalacker-Mercer A, West A, Bamman MM, Brooks JD, Myers RM, Absher D. Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome biology. Sep 1 14(9):R102. (2013)

    62. Johansson Å, Enroth S, Gyllensten U. Continuous aging of the human DNA methylome throughout the human lifespan. PloS one. Jun 27 8(6):e67378. (2013)

    63. Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging cell. Dec 14(6):924-32. (2015)

    64. Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Bürkle A, Caiafa P. Reconfiguration of DNA methylation in aging. Mechanisms of ageing and developmentNov 1 151:60-70. (2015)

    65. Tsurumi A, Li W. Global heterochromatin loss: a unifying theory of aging? Epigenetics. Jul 1 7(7):680-8. (2012)

    66. Toraño EG, Bayón GF, Del Real Á, Sierra MI, García MG, Carella A, Belmonte T, Urdinguio RG, Cubillo I, Garcia-Castro J, Delgado-Calle J. Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells. Journal of translational medicine. Dec 14(1):1-4. (2016)

    67. Nilsson O, Mitchum RD, Schrier L, Ferns SP, Barnes KM, Troendle JF, Baron J. Growth plate senescence is associated with loss of DNA methylation. Journal of endocrinology. Jul 1 186(1):241-9. (2005)

    68. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mechanisms of ageing and development. Apr 1 130(4):234-9. (2009)

    69. Bork S, Pfister S, Witt H, Horn P, Korn B, Ho AD, Wagner W. DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging cell. Feb 9(1):54-63. (2010)

    70. Koch CM, Suschek CV, Lin Q, Bork S, Goergens M, Joussen S, Pallua N, Ho AD, Zenke M, Wagner W. Specific age-associated DNA methylation changes in human dermal fibroblasts. PloS one. Feb 8 6(2):e16679. (2011)

    71. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P. Aging and replicative senescence have related effects on human stem and progenitor cells. PloS one. Jun 9 4(6):e5846. (2009)

    72. Franzen J, Zirkel A, Blake J, Rath B, Benes V, Papantonis A, Wagner W. Senescence-associated DNA methylation is stochastically acquired in subpopulations of mesenchymal stem cells. Aging cell. Feb 16(1):183-91. (2017)

    73. Koch CM, Reck K, Shao K, Lin Q, Joussen S, Ziegler P, Walenda G, Drescher W, Opalka B, May T, Brümmendorf T. Pluripotent stem cells escape from senescence-associated DNA methylation changes. Genome research. Feb 1 23(2):248-59. (2013)

    74. Koch CM, Joussen S, Schellenberg A, Lin Q, Zenke M, Wagner W. Monitoring of cellular senescence by DNA-methylation at specific CpG sites. Aging cell. Apr 11(2):366-9. (2012)

    75. Schellenberg A, Mauen S, Koch CM, Jans R, de Waele P, Wagner W. Proof of principle: quality control of therapeutic cell preparations using senescence-associated DNA-methylation changes. BMC research notes. Dec 7(1):1-5. (2014)

    76. Vogt M, Haggblom JY, Christiansen T, Haas M. Independent Induction of Senescence by p16INK4 and p21C in Spontaneously Immortalized Human Fibroblasts'. 9, 139-1466 (1998)

    77. Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. Feb 23 7(8):8524. (2016)

    78. Madrigano J, Baccarelli AA, Mittleman MA, Sparrow D, Vokonas PS, Tarantini L, Schwartz J. Aging and epigenetics: longitudinal changes in gene-specific DNA methylation. Epigenetics. Jan 1 7(1):63-70. (2012)

    79. W.S. Post, P.J. Goldschmidt-Clermont, C.C. Wilhide, A.W. Heldman, M.S. Sussman, P. Ouyang, E.E. Milliken, J.P. Issa Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system Cardiovasc. Res. 43, 985-991 (1999)

    80. So K, Tamura G, Honda T, Homma N, Waki T, Togawa N, Nishizuka S, Motoyama T. Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer science. Nov 97(11):1155-8. (2006)

    81. Colonna-Romano G, Aquino A, Bulati M, Lio D, Candore G, Oddo G, Scialabba G, Vitello S, Caruso C. Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence. Experimental gerontology. Oct 1 39(10):1439-46. (2004)

    82. Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Bürkle A, Caiafa P. Reconfiguration of DNA methylation in aging. Mechanisms of ageing and development. Nov 1 151:60-70. (2015)

    83. Marttila S, Kananen L, Häyrynen S, Jylhävä J, Nevalainen T, Hervonen A, Jylhä M, Nykter M, Hurme M. Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression. BMC genomics. Dec 1 16(1):179. (2015)

    84. Tserel L, Kolde R, Limbach M, Tretyakov K, Kasela S, Kisand K, Saare M, Vilo J, Metspalu A, Milani L, Peterson P. Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Scientific reports. Aug 19 5:13107. (2015)

    85. Wei L, Liu B, Tuo J, Shen D, Chen P, Li Z, Liu X, Ni J, Dagur P, Sen HN, Jawad S. Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell reports. Nov 29 2(5):1151-8. (2012)

    86. Zhang Z, Deng C, Lu Q, Richardson B. Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mechanisms of ageing and development. May 1 123(9):1257-68. (2002)

    87. Zhao M, Qin J, Yin H, Tan Y, Liao W, Liu Q, Luo S, He M, Liang G, Shi Y, Zhang Q. Distinct epigenomes in CD4+ T cells of newborns, middle-ages and centenarians. Scientific reports. Dec 5 6:38411. (2016)

    88. Richardson B. Impact of aging on DNA methylation. Ageing research reviews. Jul 1 2(3):245-61. (2003)

    89. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mechanisms of ageing and development. Apr 1 130(4):234-9. (2009)

    90. Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA. Distinct DNA methylomes of newborns and centenarians. Proceedings of the National Academy of Sciences. Jun 26 109(26):10522-7. (2012)

    91. Yuan T, Jiao Y, de Jong S, Ophoff RA, Beck S, Teschendorff AE. An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging. PLoS Genet. 2015 Feb 18 11(2):e1004996. Nottke A, Colaiacovo MP, Shi Y. Developmental roles of the histone lysine demethylases. Development. 136:879-889. (2009)

    92. Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans. Genes & development. Jul 1;19(13):1544-55. Genes Dev. 19:1544-1555. (2005)

    93. Li J, Ebata A, Dong Y, Rizki G, Iwata T, Lee SS. Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. Sep 30;6(9):e233. (2008)

    94. McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. Journal of Biological Chemistry Jan 4;283(1):350-7. (2008)

    95. Chen S, Whetstine JR, Ghosh S, Hanover JA, Gali RR, Grosu P, Shi Y. The conserved NAD (H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span. Proceedings of the National Academy of Sciences. Feb 3;106(5):1496-501. (2009)

    96. Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ. Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proceedings of the National Academy of Sciences. Jan 5;107(1):169-74. (2010)

    97. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011 479:365-371.

    98. Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science. 330:622-627 (2010)

    99. Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, Lane RH. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. Journal of molecular endocrinology. Aug 41(2):91. (2008)

    100. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences. Nov 4 105(44):17046-9. (2008)

    101. Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Slagboom PE, Heijmans BT. DNA methylation differences after exposure to prenatal famine are common and timing-and sex-specific. Human molecular genetics. Nov 1 18(21):4046-53. (2009)

    102. Liu Y, Murphy SK, Murtha AP, Fuemmeler BF, Schildkraut J, Huang Z, Overcash F, Kurtzberg J, Jirtle R, Iversen ES, Forman MR. Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics. Jul 1 7(7):735-46. (2012)

    103. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nature reviews genetics. Feb 13(2):97-109. (2012)

    104. Leenen FA, Muller CP, Turner JD. DNA methylation: conducting the orchestra from exposure to phenotype?. Clinical epigenetics. Dec 1 8(1):92. (2016)

    105. Aoi W, Naito Y, Mizushima K, Takanami Y, Kawai Y, Ichikawa H, Yoshikawa T. The microRNA miR-696 regulates PGC-1α in mouse skeletal muscle in response to physical activity. American Journal of Physiology-Endocrinology and Metabolism. Apr 298(4):E799-806. (2010)

    106. Keller P, Vollaard NB, Gustafsson T, Gallagher IJ, Sundberg CJ, Rankinen T, Britton SL, Bouchard C, Koch LG, Timmons JA. A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. Journal of applied physiology. Jan 110(1):46-59. (2011)

    107. Nakajima N, Takeika M, Mori M, Hashimoto S, Sakurai A, Nose H, Itano N, Shiohara M, Oh T, Taniguchi S. Exercise effects on methylation of ASC gene. Int J Sports Med. Dec 6 30:1-5. (2009)

    108. Smith JA, Kohn TA, Chetty AK, Ojuka EO. CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene. American Journal of Physiology-Endocrinology and Metabolism. Sep 295(3):E698-704. (2008)

    109. Douglas PM, Dillin A. Protein homeostasis and aging in neuro-degeneration. J. Cell Biol. 190:719-729. (2010)

    110. Frobel J, Hemeda H, Lenz M, Abagnale G, Joussen S, Denecke B, Šarić T, Zenke M, Wagner W. Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem cell reports. Sep 9 3(3):414-22. (2014)

    111. Horvath S. DNA methylation age of human tissues and cell types. Genome biology. 2013 Oct 1 14(10):3156.

    112. Koch CM, Reck K, Shao K, Lin Q, Joussen S, Ziegler P, Walenda G, Drescher W, Opalka B, May T, Brümmendorf T. Pluripotent stem cells escape from senescence-associated DNA methylation changes. Genome research. Feb 1 23(2):248-59. (2013)

    113. Weidner CI, Lin Q, Koch CM, Eisele L, Beier F, Ziegler P, Bauerschlag DO, Jöckel KH, Erbel R, Mühleisen TW, Zenke M. Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome biology. Feb 1 15(2):R24. (2014)

    114. Yen WL, Klionsky DJ. How to live long and prosper: autophagy, mitochondria, and aging. Physiology. Oct 23(5):248-62. (2008)

    115. Salminen A, Kaarniranta K. Regulation of the aging process by autophagy. Trends in molecular medicine. May 1 15(5):217-24. (2009)

    116. Petrovski G, Das DK. Does autophagy take a front seat in lifespan extension? Journal of cellular and molecular medicine. Nov 14(11):2543-51. (2010)

    117. Cuervo AM. Autophagy and aging: keeping that old broom working. Trends in Genetics. Dec 1 24(12):604-12. (2008)

    118. Zhang C. Restoration of chaperone-mediated autophagy in aging mice (Doctoral dissertation, ProQuest Dissertations & Theses). (2008)

    119. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. Sep 5 301(5638):1387-91. (2003)

    120. Hars ES, Qi H, Jin SV, Cai L, Hu C, Liu LF. Autophagy regulates ageing in C. elegans. Autophagy. Mar 27 3(2):93-5. (2007)

    121. Jia K, Levine B. Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy. Nov 26 3(6):597-9. (2007)

    122. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS genet. Feb 15 4(2):e24. (2008)

    123. Salminen A, Kaarniranta K. Regulation of the aging process by autophagy. Trends in molecular medicine. May 1 15(5):217-24. (2009)

    124. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2 146(5):682-95. (2011)

    125. Kang HT, Lee KB, Kim SY, Choi HR, Park SC. Autophagy impairment induces premature senescence in primary human fibroblasts. PloS one. Aug 8 6(8):e23367. (2011)

    126. Brunk UT, Terman A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. European Journal of Biochemistry. Apr 269(8):1996-2002. (2002)

    127. Bergamini ET, Cavallini GA, Donati A, Gori ZI. The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases. The international journal of biochemistry & cell biology. Dec 1 36(12):2392-404. (2004)

    128. Yen WL, Klionsky DJ. How to live long and prosper: autophagy, mitochondria, and aging. Physiology. Oct 23(5):248-62. (2008)

    129. Li L, Zhang X, Le W. Autophagy dysfunction in Alzheimer's disease. Neurodegenerative Diseases. 7(4):265-71. (2010)

    130. Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nature neuroscience. Jul 13(7):805-11. (2010)

    131. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and 'Garb-aging'. Trends in Endocrinology & Metabolism. Mar 1 28(3):199-212. (2017)

    132. Cuervo AM, Dice JF. Age-related decline in chaperone-mediated autophagy. Journal of Biological Chemistry. Oct 6 275(40):31505-13. (2000)

    133. Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nature medicine. Sep 14(9):959-65. (2008)

    134. Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, Fisher CC, Zhang M, Saucerman JJ, Goodyear LJ, Kundu M. AMPK phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nature communications. Sep 15 8(1):1-3. (2017)

    135. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature cell biology. Sep 13(9):1016-23. (2011)

    136. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Current opinion in cell biology. Apr 1 22(2):124-31. (2010)

    137. Mizushima N. The role of the ATG1/ULK1 complex in autophagy regulation. Current opinion in cell biology. Apr 1 22(2):132-9. (2010)

    138. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS letters. Apr 2 584(7):1287-95. (2010)

    139. Lee JW, Park S, Takahashi Y, Wang HG. The association of AMPK with ULK1 regulates autophagy. PloS one. Nov 3 5(11):e15394. (2010)

    140. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. Jan 28 331(6016):456-61. (2011)

    141. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature cell biology. Feb 13(2):132-41. (2011)

    142. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences. Mar 4 105(9):3374-9. (2008)

    143. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell metabolism. Dec 5 6(6):472-83. (2007)

    144. Sengupta A, Molkentin JD, Yutzey KE. FoxO transcription factors promote autophagy in cardiomyocytes. Journal of Biological Chemistry. Oct 9 284(41):28319-31. (2009)

    145. Miquel J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutation Research/DNAging. Sep 1 275(3-6):209-16. (1992)

    146. Luft R. The development of mitochondrial medicine. Proceedings of the National Academy of Sciences. Sep 13 91(19):8731-8. (1994)

    147. Fosslien E. Mitochondrial medicine-molecular pathology of defective oxidative phosphorylation. Annals of Clinical & Laboratory Science. Jan 1 31(1):25-67. (2001)

    148. Lee HC, Wei YH. Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Experimental biology and medicine. May 232(5):592-606. (2007)

    149. Linnane A, Ozawa T, Marzuki S, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. The Lancet. Mar 25 333(8639):642-5. (1989)

    150. Park CB, Larsson NG. Mitochondrial DNA mutations in disease and aging. Journal of cell biology. May 30 193(5):809-18. (2011)

    151. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet.. Dec 15 39:359-407. (2005)

    152. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. Jul 15 309(5733):481-4. (2005)

    153. Khrapko K, Vijg J. Mitochondrial DNA mutations and aging: a case closed? Nature genetics. Apr 39(4):445-6. (2007)

    154. Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nature genetics. Apr 40(4):392-4. (2008)

    155. Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell metabolism. Aug 6 10(2):131-8. (2009)

    156. Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PloS one. Jul 7 5(7):e11468. (2010)

    157. Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceedings of the National Academy of Sciences. Sep 1 85(17):6465-7. (1988)

    158. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. May 429(6990):417-23. (2004)

    159. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA. Mitochondrial point mutations do not limit the natural lifespan of mice. Nature genetics. Apr 39(4):540-3. (2007)

    160. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiological genomics. Dec 16 16(1):29-37. (2003)

    161. Sykiotis GP, Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Science signaling. Mar 9 3(112) (2010)

    162. Brigelius-Flohé R, Flohé L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxidants & redox signaling. Oct 15 15(8):2335-81. (2011)

    163. Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell. Mar 21 132(6):1025-38. (2008)

    164. Park SK, Tedesco PM, Johnson TE. Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging cell. Jun 8(3):258-69. (2009)

    165. Leiser SF, Miller RA. Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Molecular and cellular biology. Feb 1 30(3):871-84. (2010)

    166. Lewis KN, Mele J, Hayes JD, Buffenstein R. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integrative and comparative biology. Nov 1 50(5):829-43. (2010)

    167. Przybysz AJ, Choe KP, Roberts LJ, Strange K. Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone. Mechanisms of ageing and development. Jun 1 130(6):357-69. (2009)

    168. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. American Journal of Physiology-Heart and Circulatory Physiology. Aug 301(2):H363-72. (2011)

    169. Bloom DA, Jaiswal AK. Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD (P) H: quinone oxidoreductase-1 gene expression. Journal of Biological Chemistry. Nov 7 278(45):44675-82. (2003)

    170. Sekhar KR, Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, Freeman ML. Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for γ-glutamylcysteine synthetase. Biochemical and biophysical research communications. Apr 2 270(1):311-7. (2000)

    171. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. Journal of Biological Chemistry. Sep 10 274(37):26071-8. (1999)

    172. Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M. The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochemical Society Transactions. Feb 1 28(2):33-41. (2000)

    173. Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, Bannai S. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. Journal of Biological Chemistry. Nov 22 277(47):44765-71. (2002)

    174. Hennig P, Garstkiewicz M, Grossi S, Di Filippo M, French LE, Beer HD. The crosstalk between Nrf2 and inflammasomes. International Journal of Molecular Sciences. Feb 19(2):562. (2018)

    175. Zhang H, Davies KJ, Forman HJ. Oxidative stress response and Nrf2 signaling in aging. Free Radical Biology and Medicine. Nov 1 88:314-36. (2015)

    176. Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T. Repression of the antioxidant NRF2 pathway in premature aging. Cell. Jun 2 165(6):1361-74. (2016)

    177. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Science translational medicine. Apr 9 6(231):231ra47. (2014)

    178. Rojo de la Vega M, Zhang DD, Wondrak GT. Topical bixin confers NRF2-dependent protection against photodamage and hair graying in mouse skin. Frontiers in pharmacology. Mar 27 9:287. (2018)

    179. Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM, Steffen KK, Williams EG, Mouchiroud L, Tronnes SU, Murillo V. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell. May 19 165(5):1209-23. (2016)

    180. Ducker GS, Chen L, Morscher RJ, Ghergurovich JM, Esposito M, Teng X, Kang Y, Rabinowitz JD. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell metabolism. Jun 14 23(6):1140-53. (2016)

    181. Cartee GD, Hepple RT, Bamman MM, Zierath JR. Exercise promotes healthy aging of skeletal muscle. Cell metabolism. Jun 14 23(6):1034-47. (2016)

    182. de Lange T. Protection of mammalian telomeres. Oncogene. Jan 21(4):532-40. (2002)

    183. Sahin E, DePinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. nature. Mar 464(7288):520-8. (2010)

    184. Ben-Porath I, Weinberg RA. When cells get stressed: an integrative view of cellular senescence. The Journal of clinical investigation. Jan 1 113(1):8-13. (2004)

    185. Sahin E, DePinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. nature. Mar 464(7288):520-8. (2010)

    186. Shay JW, Wright WE. Mutant dyskerin ends relationship with telomerase. Science. Dec 17 286(5448):2284-5. (1999)

    187. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. New England Journal of Medicine. Apr 7 352(14):1413-24. (2005)

    188. Niida H, Matsumoto T, Satoh H, Shiwa M, Tokutake Y, Furuichi Y, Shinkai Y. Severe growth defect in mouse cells lacking the telomerase RNA component. Nature genetics. Jun 19(2):203-6. (1998)

    189. Blasco MA. Telomere length, stem cells and aging. Nature chemical biology. Oct 3(10):640-9. (2007)

    190. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Experimental cell research. Dec 1 25(3):585-621. (1961)

    191. Malaquin N, Tu V, Rodier F. Assessing functional roles of the senescence-associated secretory phenotype (SASP). InCellular Senescence (45-55). Humana Press, New York, NY. (2019)

    192. Bielak-Zmijewska A, Mosieniak G, Sikora E. Is DNA damage indispensable for stress-induced senescence?. Mechanisms of Ageing and Development. Mar 1 170:13-21. (2018)

    193. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nature cell biology. Apr 14(4):355-65. (2012)

    194. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. The international journal of biochemistry & cell biology. May 1 37(5):961-76. (2005)

    195. Malaquin N, Martinez A, Rodier F. Keeping the senescence secretome under control: molecular reins on the senescence-associated secretory phenotype. Experimental gerontology. Sep 1 82:39-49. (2016)

    196. Scharffetter-Kochanek K, Brenneisen P, Wenk J, Herrmann G, Ma W, Kuhr L, Meewes C, Wlaschek M. Photoaging of the skin from phenotype to mechanisms. Experimental gerontology. May 1 35(3):307-16. (2000)

    197. Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nature communications. Feb 28 3(1):1-9. (2012)

    198. Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton JP, Sansom OJ, Zender L, Keyes WM. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development. Jan 15 31(2):172-83. (2017)

    199. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. Jan 469(7330):343-9. (2011)

    200. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. The Journal of clinical investigation. Nov 1 114(9):1299-307. (2004)

    201. Dhawan S, Tschen SI, Bhushan A. Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation. Genes & development. Apr 15 23(8):906-11. (2009)

    202. Agger K, Cloos PA, Rudkjær L, Williams K, Andersen G, Christensen J, Helin K. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene-and stress-induced senescence. Genes & development. May 15 23(10):1171-6. (2009)

    203. Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes & development. May 15 23(10):1177-82. (2009)

    204. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. Sep 21 130(6):1083-94. (2007)

    205. Nelson DM, McBryan T, Jeyapalan JC, Sedivy JM, Adams PD. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging. Age. Jun 1 36(3):9637. (2014)

    206. Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. Oct 32(43):5129-43. (2013)

    207. Ohtani N. The role of SASP in tumor microenvironment. Clinical calcium. 27(6):835. (2017)

    208. Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nature Reviews Cancer. Jan 16(1):35. (2016)

    209. Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. The international journal of biochemistry & cell biology. Nov 1 34(11):1401-14. (2002)

    210. Loo TM, Miyata K, Tanaka Y, Takahashi A. Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer. Cancer Science. Feb 111(2):304. (2020)

    211. Ohtani N. Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in ageing and cancer development. The Journal of Biochemistry. Oct 1 166(4):289-95. (2019)

    212. Lopes-Paciencia S, Saint-Germain E, Rowell MC, Ruiz AF, Kalegari P, Ferbeyre G. The senescence-associated secretory phenotype and its regulation. Cytokine. May 1 117:15-22. (2019)

    213. González-Puertos VY, Maciel-Barón LÁ, Barajas-Gómez BA, López-Diazguerrero NE, Königsberg M. Involvement of phenotype secretor of senescent cells in the development of cancer, aging and the diseases associated with age. Gaceta medica de Mexico. Jul 151(4):491-500. (2015)

    214. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. The EMBO journal. Apr 20 30(8):1536-48. (2011)

    215. Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. Feb 1 5(1):1-0. (2004)

    216. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL. Senolytics improve physical function and increase lifespan in old age. Nature medicine. Aug 24(8):1246-56. (2018)

    217. Pelicci PG. Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence?. The Journal of clinical investigation. Jan 1 113(1):4-7. (2004)

    218. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging: an evolutionary perspective on immunosenescence. Annals of the new York Academy of Sciences. Jun 908(1):244-54. (2000)

    219. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mechanisms of ageing and development. Jan 1 128(1):92-105. (2007)

    220. Chung HY, Kim HJ, Jung KJ, Yoon JS, Yoo MA, Kim KW, Yu BP. The inflammatory process in aging. Reviews in Clinical Gerontology. Aug 10(3):207-22. (2000)

    221. Franceschi C. Cell proliferation, cell death and aging. Aging Clinical and Experimental Research. Sep 1 1(1):3-15. (1989)

    222. Franceschi C, Monti D, Sansoni P, Cossarizza A. The immunology of exceptional individuals: the lesson of centenarians. Immunology today. Jan 1 16(1):12-6. (1995)

    223. Franceschi C, Cossarizza A. Introduction: the reshaping of the immune system with age. International reviews of immunology. Jan 1 12(1):1-4. (1995)

    224. Pawelec G. Age and immunity: What is "immunosenescence"? Experimental gerontology. May 1 105:4-9. (2018)

    225. Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Archivum immunologiae et therapiae experimentalis. Apr 1 64(2):111-26. (2016)

    226. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transplant international. Nov 22(11):1041-50. (2009)

    227. Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. Apr 20 25(16):3066-9. (2007)

    228. Pawelec G, Effros RB, Caruso C, Remarque E, Barnett Y, Solana R. T cells and aging (update february 1999). Frontiers in Bioscience: a Journal and Virtual Library. Mar 1 4:D216-69. (1999)

    229. Pawelec G, Derhovanessian E, Larbi A, Strindhall J, Wikby A. Cytomegalovirus and human immunosenescence. Reviews in medical virology. Jan 19(1):47-56. (2009)

    230. Castle SC. Clinical relevance of age-related immune dysfunction. Clinical Infectious Diseases. Aug 1 31(2):578-85. (2000)

    231. Pawelec G, Larbi A, Derhovanessian E. Senescence of the human immune system. Journal of Comparative Pathology. Jan 1 142:S39-44. (2010)

    232. DelaRosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R. Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology. Oct 1 7(5-6):471-81. (2006)

    233. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS letters. Apr 11 579(10):2035-9. (2005)

    234. Pawelec, Graham. "Hallmarks of human "immunosenescence": adaptation or dysregulation?". 9-15. (2012)

    235. Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. European journal of immunology. Sep 23(9):2375-8. (1993)

    236. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxidants & redox signaling. Mar 1 20(7):1126-67. (2014)

    237. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxidants & redox signaling. Mar 1 8(3-4):572-81. (2006)

    238. Chung HY, Kim HJ, Kim JW, Yu BP. The inflammation hypothesis of aging: molecular modulation by calorie restriction. Annals of the New York Academy of Sciences. Apr 928(1):327-35. (2001)

    239. Ma S, Sun S, Geng L, Song M, Wang W, Ye Y, Ji Q, Zou Z, Wang S, He X, Li W. Caloric restriction reprograms the Single-Cell transcriptional landscape of rattus norvegicus aging. Cell. Feb 27. 180, 1-18 (2020)

    240. Jackaman C, Tomay F, Duong L, Razak NB, Pixley FJ, Metharom P, Nelson DJ. Aging and cancer: The role of macrophages and neutrophils. Ageing research reviews. Jul 1 36:105-16. (2017)

    241. Baylis D, Bartlett DB, Patel HP, Roberts HC. Understanding how we age: insights into inflammaging. Longevity & healthspan. Dec 2(1):1-8. (2013)

    242. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. nature. Jan 481(7381):278-86. (2012)

    243. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. Journal of leukocyte biology. Sep 76(3):509-13. (2004)

    244. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature medicine. Feb 17(2):179. (2011)

    245. Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative stress, inflammaging and immunosenescence. Journal of proteomics. Oct 19 74(11):2313-23. (2011)

    246. Rando TA. Stem cells, ageing and the quest for immortality. Nature. Jun 441(7097):1080-6. (2006)

    247. Liu L, Rando TA. Manifestations and mechanisms of stem cell aging. Journal of Cell Biology. Apr 18 193(2):257-66. (2011)

    248. Cordero MD, Williams MR, Ryffel B. AMP-activated protein kinase regulation of the NLRP3 inflammasome during aging. Trends in Endocrinology & Metabolism. Jan 1 29(1):8-17. (2018)

    249. Mejias NH, Martinez CC, Stephens ME, de Rivero Vaccari JP. Contribution of the inflammasome to inflammaging. Journal of Inflammation. Dec 15(1):1-0. (2018)

    250. Minton K. Inflammasome-related ageing. Nature Reviews Immunology. Feb 17(2):77-. (2017)

    251. Rudin E, Barzilai N. Inflammatory peptides derived from adipose tissue. Immunity & Ageing. Dec 1 2(1):1. (2005)

    252. Trayhurn P, Drevon CA, Eckel J. Secreted proteins from adipose tissue and skeletal muscle-adipokines, myokines and adipose/muscle cross-talk. Archives of physiology and biochemistry. May 1 117(2):47-56. (2011)

    253. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. British journal of nutrition. Sep 92(3):347-55. (2004)

    254. de Heredia FP, Gómez-Martínez S, Marcos A. Obesity, inflammation and the immune system. Proceedings of the Nutrition Society. May 71(2):332-8. (2012)

    255. Agarwal S, Busse PJ. Innate and adaptive immunosenescence. Annals of Allergy, Asthma & Immunology. Mar 1 104(3):183-90. (2010)

    256. Conboy IM, Rando TA. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell cycle. Jun 15 11(12):2260-7. (2012)

    257. Gruber R, Koch H, Doll BA, Tegtmeier F, Einhorn TA, Hollinger JO. Fracture healing in the elderly patient. Experimental gerontology. Nov 1 41(11):1080-93. (2006)

    258. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ. Increasing p16 INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. Sep 443(7110):448-52. (2006)

    259. Goodell MA, Rando TA. Stem cells and healthy aging. Science. Dec 4 350(6265):1199-204. (2015)

    260. Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W, Li Y. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell research. Feb 26(2):190-205. (2016)

    261. Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. Jun 5 348(6239):1160-3. (2015)

    262. Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T. Repression of the antioxidant NRF2 pathway in premature aging. Cell. Jun 2 165(6):1361-74. (2016)

    263. Rafalski VA, Ho PP, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LM, Ibrahim A, Baker SJ, Barres BA, Steinman L. Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology. Jun 15(6):614-24. (2013)

    264. Ryall JG, Dell'Orso S, Derfoul A, Juan A, Zare H, Feng X, Clermont D, Koulnis M, Gutierrez-Cruz G, Fulco M, Sartorelli V. The NAD+-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell stem cell. Feb 5 16(2):171-83. (2015)

    265. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. Jun 6 153(6):1194-217. (2013)

    266. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. Jun 447(7145):725-9. (2007)

    267. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune system. Current opinion in immunology. Aug 1 22(4):507-13. (2010)

    268. Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, Le Beau MM. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature. Aug 512(7513):198-202. (2014)

    269. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 INK4a. Nature. Sep 443(7110):421-6. (2006)

    270. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. Jun 447(7145):686-90. (2007)

    271. Cheng T, Rodrigues N, Shen H, Yang YG, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. Mar 10 287(5459):1804-8. (2000)

    272. Kippin TE, Martens DJ, van der Kooy D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes & development. Mar 15 19(6):756-67. (2005)

    273. Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nature reviews Molecular cell biology. Sep 8(9):703-13. (2007)

    274. Flores I, Cayuela ML, Blasco MA. Effects of telomerase and telomere length on epidermal stem cell behavior. Science. Aug 19 309(5738):1253-6. (2005)

    275. Michan S. Calorie restriction and NAD⁺/sirtuin counteract the hallmarks of aging. Frontiers in Bioscience (Landmark Edition). Jun 1 19:1300-19. (2014)

    276. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. Aug 11 166(4):822-39. (2016)

    277. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nature reviews Molecular cell biology. Oct 16(10):593-610. (2015)

    278. Booth LN, Brunet A. The aging epigenome. Molecular cell. Jun 2 62(5):728-44. (2016)

    279. Pal S, Tyler JK. Epigenetics and aging. Science advances. Jul 1 2(7):e1600584. (2016)

    280. Fontana L, Partridge L, Longo VD. Extending healthy life span-from yeast to humans. science. Apr 16 328(5976):321-6. (2010)

    281. Muthuswami R. The Epigenome of Aging. InModels, Molecules and Mechanisms in Biogerontology 135-158. Springer, Singapore. (2020)

    282. Tatar M, Sedivy JM. Mitochondria: masters of epigenetics. Cell. May 19 165(5):1052-4. (2016)

    283. Berger SL, Sassone-Corsi P. Metabolic signaling to chromatin. Cold Spring Harbor perspectives in biology. Nov 1 8(11):a019463. (2016)

    284. Igarashi M, Guarente L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell. Jul 14 166(2):436-50. (2016)

    285. Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV, Figueroa ME, Passegué E. Autophagy maintains the metabolism and function of young and old stem cells. Nature. Mar 543(7644):205-10. (2017)

    286. Hou J, Han ZP, Jing YY, Yang X, Zhang SS, Sun K, Hao C, Meng Y, Yu FH, Liu XQ, Shi YF. Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells. Cell death & disease. Oct 4(10):e844. (2013)

    287. Tang AH, Rando TA. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. The EMBO Journal. Dec 1 33(23):2782-97. (2014)

    288. Gopinath SD, Webb AE, Brunet A, Rando TA. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem cell reports. Apr 8 2(4):414-26. (2014)

    289. Paik JH, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS, Chae SS, Zheng H, Ying H, Mahoney J, Hiller D. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell stem cell. Nov 6 5(5):540-53. (2009)

    290. Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD. FoxO3 regulates neural stem cell homeostasis. Cell stem cell. Nov 6 5(5):527-39. (2009)

    291. Webb AE, Pollina EA, Vierbuchen T, Urbán N, Ucar D, Leeman DS, Martynoga B, Sewak M, Rando TA, Guillemot F, Wernig M. FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis. Cell reports. Aug 15 4(3):477-91. (2013)

    292. Webb AE, Kundaje A, Brunet A. Characterization of the direct targets of FOXO transcription factors throughout evolution. Aging cell. Aug 15(4):673-85. (2016)

    293. Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell metabolism. Jun 14 23(6):990-1003. (2016)

    294. García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, Sandri M. Autophagy maintains stemness by preventing senescence. Nature. Jan 529(7584):37-42. (2016)

    295. Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, Brunson C, Mastey N, Liu L, Tsai CR, Goodell MA. mTORC1 controls the adaptive transition of quiescent stem cells from G 0 to G Alert. Nature. Jun 510(7505):393-6. (2014)

    296. Ferrón SR, Marqués-Torrejón MÁ, Mira H, Flores I, Taylor K, Blasco MA, Farinas I. Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. Journal of Neuroscience. Nov 18 29(46):14394-407. (2009)

    297. Flores I, Canela A, Vera E, Tejera A, Cotsarelis G, Blasco MA. The longest telomeres: a general signature of adult stem cell compartments. Genes & development. Mar 1 22(5):654-67. (2008)

    298. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature medicine. Jun 13(6):742-7. (2007)

    299. Lee HW. Blasco MA, Gottlieb GJ, Horner JW 2nd, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature. 392:569-74. (1998)

    300. Chandel NS, Jasper H, Ho TT, Passegue E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nature cell biology. Aug 18(8):823-32. (2016)

    301. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. Dec 4 350(6265):1208-13. (2015)

    302. Imai SI, Guarente L. NAD+ and sirtuins in aging and disease. Trends in cell biology. Aug 1 24(8):464-71. (2014)

    303. Diaz-Ruiz A, Gonzalez-Freire M, Ferrucci L, Bernier M, De Cabo R. SIRT1 synchs satellite cell metabolism with stem cell fate. Cell stem cell. Feb 5 16(2):103-4. (2015)

    304. Hwang IY, Kwak S, Lee S, Kim H, Lee SE, Kim JH, Kim YA, Jeon YK, Chung DH, Jin X, Park S. Psat1-dependent fluctuations in α-ketoglutarate affect the timing of ESC differentiation. Cell metabolism. Sep 13 24(3):494-501. (2016)

    305. Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D, Padilla PG, Ables G, Bamman MM, Thalacker-Mercer AE, Nichenametla SN. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell metabolism. Nov 3 22(5):861-73. (2015)

    306. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer JJ, Zhu H, Asara JM. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science. Jan 11 339(6116):222-6. (2013)

    307. Prozorovski T, Ingwersen J, Lukas D, Göttle P, Koop B, Graf J, Schneider R, Franke K, Schumacher S, Britsch S, Hartung HP. Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells. Neuroscience Letters. Jun 21 704:116-25. (2019)

    308. Tasselli L, Zheng W, Chua KF. SIRT6: novel mechanisms and links to aging and disease. Trends in Endocrinology & Metabolism. Mar 1 28(3):168-85. (2017)

    309. Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, Haynes CM, Chen D. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science. Mar 20 347(6228):1374-7. (2015)

    310. Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. Nov 491(7425):603-7. (2012)

    311. Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell. Jan 20 148(1-2):46-57. (2012)

    312. Lavasani M, Robinson AR, Lu A, Song M, Feduska JM, Ahani B, Tilstra JS, Feldman CH, Robbins PD, Niedernhofer LJ, Huard J. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nature communications. Jan 3 3(1):1-2. (2012)

    313. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. Jun 6 153(6):1194-217. (2013)

    314. Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. Apr 472(7342):221-5. (2011)

    315. Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD, Dubova I. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell stem cell. Jun 3 8(6):688-94. (2011)

    316. Nehlin JO, Skovgaard GL, Bohr VA. The Werner syndrome: a model for the study of human aging. Annals of the New York Academy of Sciences. Jun 908(1):167-79. (2000)

    317. Liu GH, Suzuki K, Li M, Qu J, Montserrat N, Tarantino C, Gu Y, Yi F, Xu X, Zhang W, Ruiz S. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nature communications. Jul 7 5(1):1-7. (2014)

    318. Kudlow BA, Kennedy BK, Monnat RJ. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature reviews Molecular cell biology. May 8(5):394-404. (2007)

    319. Guerville F, Barreto PD, Ader I, Andrieu S, Casteilla L, Dray C, Fazilleau N, Guyonnet S, Langin D, Liblau R, Parini A. Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. The Journal of prevention of Alzheimer's disease. Jan 1:1-9. (2020)

    320. Miquel J, Lundgren PR, Bensch KG, Atlan H. Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster. Mechanisms of ageing and development. Jan 1 5:347-70. (1976)

    321. Micó V, Berninches L, Tapia J, Daimiel L. NutrimiRAging: micromanaging nutrient sensing pathways through nutrition to promote healthy aging. International journal of molecular sciences. May 18(5):915. (2017)

    322. Cummings NE, Lamming DW. Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Molecular and cellular endocrinology. Nov 5 455:13-22. (2017)

    323. Tabibzadeh S. Nature creates, adapts, protects and sustains life using hydrogen sulfide. Frontiers in bioscience (Landmark edition). Jan 21:528-60. (2016)

    324. Jayarathne S, Ramalingam L, Edwards H, Vanapalli SA, Moustaid-Moussa N. Tart Cherry Increases Lifespan in Caenorhabditis elegans by Altering Metabolic Signaling Pathways. Nutrients. May 12(5):1482. (2020)

    325. García-Segura L, Pérez-Andrade M, Miranda-Ríos J. The emerging role of MicroRNAs in the regulation of gene expression by nutrients. Lifestyle Genomics. 6(1):16-31. (2013)

    326. Choi SW, Claycombe KJ, Martinez JA, Friso S, Schalinske KL. Nutritional epigenomics: a portal to disease prevention. 4, 530-532 (2013)

    327. Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. International journal of molecular sciences. Oct 17(10):1712. (2016)

    328. Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M. Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovascular research. Mar 15 93(4):555-62. (2012)

    329. Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clinical chemistry. Jan 1 61(1):56-63. (2015)

    330. Serna E, Gambini J, Borras C, Abdelaziz KM, Belenguer A, Sanchis P, Avellana JA, Rodriguez-Manas L, Vina J. Centenarians, but not octogenarians, up-regulate the expression of microRNAs. Scientific reports. 2 Dec 11;2:961. (2012)

    331. Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proceedings of the national academy of sciences. May 31 108(22):9232-7. (2011)

    332. Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K. Modulation of microRNA processing by p53. Nature. Jul 460(7254):529-33. (2009)

    333. Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernández-Hernando C. MiR-33 contributes to the regulation of cholesterol homeostasis. science. Jun 18 328(5985):1570-3. (2010)

    334. Saeidimehr S, Ebrahimi A, Saki N, Goodarzi P, Rahim F. MicroRNA-based linkage between aging and cancer: from epigenetics view point. Cell Journal (Yakhteh). Jul 18(2):117. (2016)

    335. Frost RJ, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proceedings of the National Academy of Sciences. Dec 27 108(52):21075-80. (2011)

    336. Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A. The Lin28/let-7 axis regulates glucose metabolism. Cell. Sep 30 147(1):81-94. (2011)

    337. Sebastiani G, Po A, Miele E, Ventriglia G, Ceccarelli E, Bugliani M, Marselli L, Marchetti P, Gulino A, Ferretti E, Dotta F. MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetologica. Jun 1 52(3):523-30. (2015)

    338. Li YQ, Zhang MF, Wen HY, Hu CL, Liu R, Wei HY, Ai CM, Wang G, Liao XX, Li X. Comparing the diagnostic values of circulating microRNAs and cardiac troponin T in patients with acute myocardial infarction. Clinics. Jan 68(1):75-80. (2013)

    339. Goren Y, Kushnir M, Zafrir B, Tabak S, Lewis BS, Amir O. Serum levels of microRNAs in patients with heart failure. European journal of heart failure. Feb 14(2):147-54. (2012)

    340. Tijsen AJ, Creemers EE, Moerland PD, de Windt LJ, van der Wal AC, Kok WE, Pinto YM. MiR423-5p as a circulating biomarker for heart failure. Circulation research. Apr 2 106(6):1035. (2010)

    341. Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-κB signaling. Journal of molecular cell biology. Jun 1 3(3):159-66. (2011)

    342. Frasca D, Diaz A, Romero M, Ferracci F, Blomberg BB. MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals. The Journal of Immunology. Sep 1 195(5):2134-40. (2015)

    343. Jin K. Modern biological theories of aging. Aging and disease. Oct 1(2):72. (2010)

    344. Brys K, Vanfleteren JR, Braeckman BP. Testing the rate-of-living/oxidative damage theory of aging in the nematode model Caenorhabditis elegans. Experimental gerontology. Sep 1 42(9):845-51. (2007)

    345. Bjorksten J. The crosslinkage theory of aging. Journal of the American Geriatrics Society. Apr 16(4):408-27. (1968)

    346. Bjorksten J, Tenhu H. The crosslinking theory of aging-Added evidence. Experimental gerontology. Jan 1 25(2):91-5. (1990)

    347. Gerschman R. Oxygen poisoning and x-irradiation: a mechanism in common. In: Glutathione Jan 1 (288-291). Academic Press. (1954)

    348. Blagosklonny MV. Selective anti-cancer agents as anti-aging drugs. Cancer biology & therapy. Dec 1 14(12):1092-7. (2013)

    349. Blagosklonny MV. Aging is not programmed: genetic pseudo-program is a shadow of developmental growth. Cell cycle. Dec 15 12(24):3736-42. (2013)

    350. Blagosklonny MV. Rapamycin extends life-and health span because it slows aging. Aging (Albany NY). Aug 5(8):592. (2013)

    351. Kobayashi T. A new role of the rDNA and nucleolus in the nucleus-rDNA instability maintains genome integrity. Bioessays. Mar 30(3):267-72. (2008)

    352. D'Aquila P, Montesanto A, Mandalà M, Garasto S, Mari V, Corsonello A, Bellizzi D, Passarino G. Methylation of the ribosomal RNA gene promoter is associated with aging and age-related decline. Aging Cell. Oct 16(5):966-75. (2017)

    353. Sanokawa-Akakura R, Akakura S, Ostrakhovitch EA, Tabibzadeh S. Replicative senescence is distinguishable from DNA damage-induced senescence by increased methylation of promoter of rDNA and reduced expression of rRNA. Mechanisms of Ageing and Development. Oct 1 183:111149. (2019)

    354. Cairns J. Mutation selection and the natural history of cancer. Nature. May 255(5505):197-200. (1975)

    355. Potten CS, Hume WJ, Reid P, Cairns J. The segregation of DNA in epithelial stem cells. Cell. Nov 1 15(3):899-906. (1978)

    356. Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. Journal of cell science. Jun 1 115(11):2381-8. (2002)

    357. Conboy MJ, Karasov AO, Rando TA. High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol. Apr 17 5(5):e102. (2007)

    358. Shinin V, Gayraud-Morel B, Gomès D, Tajbakhsh S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature cell biology. Jul 8(7):677-82. (2006)

    359. Karpowicz P, Morshead C, Kam A, Jervis E, Ramunas J, Cheng V, Van Der Kooy D. Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. The Journal of cell biology. Aug 29 170(5):721-32. (2005)

    360. Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development. Feb 15 132(4):681-7. (2005)

    361. Karpowicz P, Pellikka M, Chea E, Godt D, Tepass U, van der Kooy D. The germline stem cells of Drosophila melanogaster partition DNA non-randomly. European journal of cell biology. Jul 1 88(7):397-408. (2009)

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Siamak Tabibzadeh. Cell-centric hypotheses of aging. Frontiers in Bioscience-Landmark. 2021. 26(1); 1-49.