A review about longevity

Biological causes of aging and lifespan limitation. The more we learn about aging, the more it seems like it might not be an inescapable consequence of life. A striking fact is that aging rates vary dramatically from one species to the other, and from one individual to the other within one species. Some species age so slow that individuals systematically die of starvation, disease, accident or predation before showing any sign of senescence. It is thus tempting to imagine that a better knowledge of the determinants of lifespan could enable us to delay aging.

Aging long long life

But could we reverse it?

Different perceptions of aging compete among scientists. Does aging follow a purposeful pattern driven by genes? Does it happen through random coincidental events? According to the evolution theory, all biological processes are genetically programmed from the beginning of life to reproductive maturity. Beyond this point, biologists are in disagreement as to whether genes further drive the organism into aging or whether aging stems from a stochastic accumulation of damage affecting molecular fidelity [1]. Aging thus defies a universally accepted definition.

Dr L. Hayflick

deplores that this leads to failures in communication and interpretation of research results [2]. He advocates a stochastic approach of aging and a deterministic view of longevity [2] [3]:



“Entropy explains aging, genetic determinism explains longevity, andundefined terminology explains misunderstanding both.”

L. Hayflick

The maintenance theory noticed that aging becomes manifest when molecular and cellular repair and replacement systems are no longer able to maintain the balance that existed before reproductive maturation. Some argue that this balance must ultimately fail because of increasing entropy [8].

Advocates of the disposable soma and the antagonistic pleiotropy theory see aging as a negative but inevitable side effect of necessary functions. Williams, who conceived the latter, wrote that natural selection could favor fitness in youth at the expense of fitness later on in life [9]:

biological-causes-of-human-aging-and-lifespan-limitation-a-review-about-longevity“Natural selection may be said to be biased in favor of youth over old age whenever a conflict of interests arises.”

G. Williams

Other theories, suggesting that aging might be the result of a trade-off between some quality that produces a benefit in an organisms youth and disadvantage during old age, followed suit [10]. But why then does gene expression dramatically change during aging ? Inspired by the controversial group selection theory, scientists have shown that aging could benefit to survival of a group although compromising individual fitness. This point supports the programmed aging theories. As Wilson noticed in 1974 [11]:

“[To speak of programming] is to postulate that there are direct or indirect advantages of limiting life span through aging.”



To learn more about this debate and its implications :

Aging can be tackled at different levels. First, there is a loss in molecular fidelity, so that some talk about molecular aging. Second, there is the aging of each cell, known as cell senescence. Cell senescence is a crucial mechanism for development but becomes deleterious when it affects stem and immune cells function, challenging tissue homeostasis. Aging is thus characterized by a changing phenotype at tissue and organ level. Recently, the hypothesis that aging could be driven by systemic factors has triggered intense scientific investigation.

This review examines the biological main causes of aging targeted by experimental anti-aging therapies. For complementary information, you can read The Hallmarks of Aging from Cell [12].



Genome damage, a limit to longevity?

DNA damage accumulates throughout life, because of the many factors that threaten genome stability. They include extrinsic physical, chemical, and biological agents, as well as intrinsic threats (DNA replication errors, hydrolytic reactions, and reactive oxygen species) [13]. Deficiencies in DNA repair mechanisms cause accelerated aging in mice and humans, suggesting causal links between accumulation of nuclear DNA damage and aging [13] [14] [15].

research-companies-human-longevity-and-life-spanMitochondrial DNA damage. There is evidence of the implication of mitochondrial DNA (mtDNA) mutations in aging: deterioration of mtDNA through mutations [16] or defection of mtDNA polymerase [17] [18] [19] can induce premature aging or reduced lifespan. But whether mtDNA is more or less vulnerable to damage than nuclear DNA remains controversial. Besides, the multiple copies of mtDNA in each cell probably attenuate the consequences of mtDNA damage. Interestingly, the number of mitochondria decreases with age in liver cells of mice [20], rats [21], and humans [22] [23], consistent with a decrease in mtDNA copy number [24]. This could explain why mutation accumulation in mitochondrial genome might eventually become significant in the aging process. Another explanation is that accumulation of cells that contain high levels of mutant mtDNA could be an inevitable result of the normal mechanisms that maintain cellular concentrations of mtDNA [25].

Nuclear DNA damage. Somatic mutations and chromosomal anomalies are more likely to be observed in aged than young organisms [26] [27] [28]. DNA alterations eventually affect crucial genes or transcriptional pathways. As a result, cells dysfunction and may jeopardize tissue and organismal homeostasis, if not eliminated by apoptosis or senescence. Age-associated defects in the nuclear lamina may also aggravate genomic damage [29].

Recent studies suggest that nuclear DNA repair pathways might be involved in the aging process. The NAD+-dependent (1) poly(ADP-ribose) polymerase proteins (PARP) are usually associated with DNA repair mechanism. Recent studies have also linked them to mitochondrial function (4) and oxidative metabolism [30] [31]. PARP activation influences cellular metabolism through alterations in NAD+ (1) metabolism, direct PARylation events (a PARP-dependent post-translational alteration) and transcriptional reprogramming of the cell [31]. In general, PARP inhibition enhances oxidative metabolism and mitochondrial content (4). Interestingly, enhanced PARP activity is observed in aged organisms [32]. PARP-1 is an abundant nuclear enzyme activated by DNA damage and involved in repair mechanisms. Its activation may lead to rapid depletion of the cytosolic NAD+ (1) pool, and could even induce cell apoptosis [33] in case of massive DNA damage.

Another DNA damage response pathway is directed by tumor suppressor p53 (3). Interestingly, p53 can promote longevity by preventing the development of cancer, but increased p53 activation can have deleterious effects. It could promote aspects of the aging process by challenging tissue homeostasis with excessive senescence
or apoptosis signaling [34] ( see ”Cellular senescence” and ”Telomere shortening”).

As DNA damage accumulates with chronological age, the consumption of NAD+ (1) by PARP proteins increases. Sirtuins (2) activity is likely to be disturbed by NAD+ pool depletion. As for p53 (3), its overexpression in aging cells could be induced by PARP activation [35].

One interpretation is that DNA damage accumulation might be a biological clock driven by increasing entropy. DNA damage could be exponentially growing because it eventually affects genes encoding replication and repair mechanism, which thus become less efficient in faithfully replicating the DNA. With excessive activation of PARP, PARP-induced mechanism, designed to protect the organism against DNA damaged cell, may eventually deplete the NAD+ (1) pool and undermine NAD+-dependent sirtuins (2) function [36]. Although the role of sirtuins in the aging process is not fully unraveled yet, this alteration could have multiple consequences on cell metabolism.


Telomere shortening: Programmed cellular senescence?

DNA deterioration affects the genome almost randomly. But some chromosomal regions are particularly sensitive to aging-associated damage [37]. Replicative DNA polymerases do not replicate thoroughly the end of linear DNA molecules. This function is exclusively carried out by a special DNA polymerase known as telomerase. In humans, telomerase is only expressed in embryonic stem cells (enabling them to divide repeatedly), certain adult stem cells, and tumoral cells. Most somatic cells of mammals do not express telomerase. This leads to the progressive and cumulative loss of chromosome ends during cell cycles, and eventually entails cell senescence [38]. Telomerase deficiency in humans is associated with premature development of diseases (pulmonary fibrosis, dyskeratosis congenita, and aplastic anemia) which involve the loss of the regenerative capacity of different tissues [39].

biological-causes-of-human-aging-and-lifespan-limitation-a-review-about-longevitySeveral mechanisms are involved in regulating telomere replication. Shelterin is a protein complex that binds telomeres and regulates their replication [40] [41]. Loss-of-function models for shelterin components result in rapid decline of the regenerative capacity of tissues and accelerated aging [42]. Sirtuins are suspected to play a role in telomere maintenance [43] through epigenetic modulations. SIRT-6 modulates telomeric chromatin [44] and cell cycle [45].

Critically short telomere length could activate a DNA damage response pathway involving p53 and p21WAF1 in aging cells [46]. p53 protein DNA binding and transcriptional activity increases with age, and p21WAF1 promoter activity in senescent cells is dependent on p53. Moreover, PARP could be involved in the post-translational activation of p53 in aging cells : p53 protein can associate with PARP, and inhibition of PARP activity leads to suppression of p21 expression in response to DNA damage [46]. PARP activation is associated with accelerated telomere loss and premature senescence [47].

Telomere shortening is often depicted as a biological clock for somatic cells, triggering cellular senescence. It looks like another anti-cancer strategy because it prevents  cells from proliferating endlessly. This mechanism could thus promote early-life survival by reducing the development of cancer, but eventually challenge tissue homeostasis by triggering excessive senescence. Although it is sometimes interpreted as a programmed senescence mechanism (see ”Cellular senescence”), its role in phenotypic aging has not been clearly established.


Epigenetics as a key factor of lifespan control

Epigenetic mechanisms. Source : http://en.wikipedia.org/wiki/Epigenetics

Epigenetics is at the core of the aging process because it describes changes in cellular activity overtime through modulation of transcriptional pathways. Epigenetic alterations are induced by a complex enzymatic system ensuring the maintenance and the evolution of epigenetic patterns. They are associated with the activation of inflammatory genes and the development of age-related disease (cancer, dementia and atherosclerosis).


DNA methylation. There is an age-associated hypo- or hypermethylation of particular loci of the DNA [48]. On a gene promoter, methylation acts to repress gene transcription. Hypomethylation could increase DNA mutation rate. Hypermethylated genes with age include genes encoding estrogen receptor, insulin-like growth factor 2 (IGF-2), and tumor suppressor [48]. Remarkably, DNA methylation patterns modifications may particularly affect stem cells [49]. However, there is no experimental demonstration that lifespan can be extended by modifying DNA methylation patterns.

Chromatin remodeling. With age, there is a decrease in levels of chromatin remodeling factors [49] [50], as well as a loss or redistribution of global heterochromatin. Studies have found evidence of connection between heterochromatin formation and chromosomal stability [51]. Chromosome ends are assembled into heterochromatin domains [52] [53] so that epigenetic alterations can influence the regulation of telomere length.

Histone modifications. Deletion of components of histone methylation complexes extends longevity in invertebrates [54] [55]. Inhibition of histone demethylases in worms may extend lifespan by targeting components of key longevity routes (like IIS) [56]. Sirtuins SIRT-1, 6 and 7 (2) play a crucial role in histone modifications. In mammals, the benefits of SIRT-1 overexpression would include improved genomic stability [57] [58]. SIRT-6 regulates genomic stability, NF-κB signaling, and glucose homeostasis through histone deacetylation [59] [60] [61].

Transcriptional alterations. Age-associated increase in transcriptional noise [62] induces overproduction and maturation of mRNAs [63] [64] and miRNAs (see A systemic approach of aging – miRNAs). Transcriptional changes for genes encoding components of inflammatory, mitochondrial and lysosomal degradation pathways [65] show once again how intertwined the different hallmarks can be.


Aging and the deterioration of the unfolded protein response

Aging and many age-related diseases, in particular degenerative diseases (Alzheimer’s disease and age-related macular degeneration), have been associated with the cellular accumulation and aggregation of unfolded proteins [66], causing the cell to dysfunction. Protein homeostasis is balanced by complex intra-cellular mechanisms. In response to stress, those mechanisms are adapted to preserve functionality of the proteome.

Chaperone proteins play a key-role in protein folding, assembly, transport and targeting for degradation [67]. Age-associated changes challenge their activity and their synthesis [68] , inducing problems in protein quality control. Old organisms feature deteriorated ATP supply (see “Mitochondrial dysfunction”) that may interfere in chaperone function. Modifications in the substrate protein (for instance accumulation of advanced glycation end-products through non-enzymatic modifications [69]) can disrupt the chaperone’s ability to identify its target.

Pharmacological or genetic manipulations that increase lifespan in model organisms often stimulate autophagy (5) [70] [71]. Autophagy inhibition compromises the positive effects of CR, SIRT1 activation, inhibition of IIS, and administration of rapamycin, resveratrol, or spermidine [71] [72].


Several integrated pathways coregulate the degradation of proteins. Aging has a negative effect on the cross-talk between them [73] [74]. The aging-related deficiency of signaling pathways (insulin-like growth factor 1 (IGF-1) pathway, ensuring cross-talk between proteasome and autophagy (5)

The maintenance of mitochondrial proteostasis is challenging because of high levels of ROS species in this organelle. The most common way of eliminating dysfunctioning mitochondria may be autophagic degradation [75], known as mitophagy. However, numerous studies have reported dysfunctioning of mitochondrial clearance in aging and age-related disorders [76]. The mitochondrial Unfolded Protein Response (mtUPR) is activated when unfolded or misfolded proteins accumulate in the mitochondria [77] [78]. Studies show that communication between mitochondria and nucleus can induce the expression of nuclear genes encoding for mitochondrial proteins in response to impaired proteostasis [79] [80]. Mitochondria-nucleus communication failures could therefore be involved in the debilitation of mitochondrial proteostasis (see “Mitochondrial dysfunction”).

The mitochondrial sirtuin SIRT-3 (2), a protein deacylase, influences almost every major aspect of mitochondrial biology (including nutrient oxidation, ATP generation, ROS detoxification, mitochondrial dynamics, mtUPR) [81]. Proteotoxic stress induced by loss of mitochondrial proteostasis activates SIRT-3 and the antioxidant defense mechanisms of mitochondria [82]. The expression of SIRT-7, a component of the regulatory branch of the mtUPR, is reduced in aged hematopoietic stem cells, and its overexpression in this setting can improve the regenerative capability of these cells [83].


Mitochondria become dysfunctional with age

The oxidative stress theory (also known as free radical theory) argues that age-related mitochondrial dysfunction stems from high levels of reactive oxygen species (ROS) in the mitochondria (4) [84]. But the role of oxidative stress is likely to have been misunderstood during the early stages of research on aging. Recent experiments have shown that increased ROS levels may actually extend lifespan [85] [86] [87], whereas enhanced antioxidant defense did not [88]. Moreover, ROS have been found to spark off proliferation and survival responses in stress conditions [89]. The exact mechanism of ROS and oxidative stress-induced age-related pathologies is not yet very clear. They could for instance stimulate autophagy (5)

ROS could be regarded as a stress-induced survival signal. During aging, cellular stress and damage increase. The levels of ROS increase in parallel in an attempt to maintain survival. Beyond a certain point, ROS levels betray their homeostatic purpose, and eventually, they could aggravate age-associated damage [92].

research-companies-human-longevity-and-life-spanMitonchondrial dysfunction seems to be a hallmark of aging. Remarkably, the mitochondrial OXPHOS metabolic pathway is disrupted during aging prior to significant mtDNA damage [93] : this suggests that mtDNA damage alone cannot account for mitochondrial dysfunction. Other causes have thus been studied. Mitochondria-nucleus communications are needed for mitochondria biogenesis and mitochondrial response to stress pathways [94]. Alterations of those communication pathways could trigger mitochondiral dysfunction.

As chronological age advances, sirtuins (2) are deactivated. SIRT-1 and 3 downregulate HIF-1α (6) [93] [95] [96]. The downmodulation of HIF-1α induces production of mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription. The depletion of the NAD+ pool (1) could then explain the deregulation of mitochondrial expression and OXPHOS disruption [93].

Sirtuins (2) are also involved in mitochondrial regulation through activation of PGC-1α(6) [97] [98]. Nucleotide excision DNA repair disorder triggers mitochondrial abnormalities that appear to be caused by decreased activation of the NAD/SIRT-1/PGC-1α axis through hyperactivation of the DNA damage sensor PARP-1 [99] (see “Genome damage”). p53 (3) expression can also repress PGC-1α and deregulate mitochondrial function, for instance as a result of telomere attrition [100].

Whether age-related mitochondrial dysfunction occurs through a PGC-1α– dependent, HIF-1α-dependent pathway, or a combination of both, is not clear yet.

Mitochondria (4) dysfunction could be induced by alteration of nuclear-mitochondria communication, possibly through mitochondrial sirtuins (2) activity deregulation. It has many negative effects on cell metabolism due to mitochondria’s crucial role in cell energetics and metabolism. For instance, it could provoke mismanagement of apoptosis and trigger inflammatory reactions [101].


Nutrient sensing: The benefits of calorie restriction for lifespan extention

Nutrient-sensing pathways adapt cell behaviour, metabolism, growth, development, and longevity to nutrient levels. One of them, the insulin/IGF-1 signaling (IIS) pathway is involved in glucose sensing and is linked to longevity. Hormone IGF-1 is produced in response to growth hormone (GH). Diverse genetic manipulations that attenuate signaling intensity at some point in the pathway (GH, IGF-1, AKT or FoxO) resulted in extended lifespan in worms, flies and mice. Multiple data suggest that calorie restrictions (CR)(7)

Other interconnected nutrient-sensing pathways include sirtuins (2), AMPK, and mTOR. AMPK and SIRT1 signal nutrient scarcity, whereas mTOR senses high amino acid concentrations. Sirtuins sense low energy states by detecting high NAD+ levels, and AMPK senses high energy states by detecting high AMP levels. Accordingly, their upregulation favors healthy aging. SIRT1 and AMPK responses are coordinated [106]. AMPK activation shuts off mTORC1 [107]. Metformin administration may extend lifespan through AMPK activation in worms and mice [108] [109] [110]. Rapamycin administration extends lifespan through mTOR inhibition [111]. As SIRT-1 activates PGC-1α (6) [98], PGC-1α could establish a connection between nutrient sensing and mitochondrial function.

Fasting also triggers lower PARP activity [112]. This reinforces the hypothesis that sirtuins (2) and PARP proteins “compete” for the cellular NAD+ pool (1).


Catalytic activities and subcellular localization of mammalian sirtuins. Credit to David B. Lombard and Surinder Kumar, Mitochondrial sirtuins and their relationships with metabolic disease and cancer, 2015.

Paradoxically, low IIS is typical of normal aging phenotypes, whereas constitutively decreased IIS extends lifespan. A model in which decreased IIS is a defensive response to systemic damage can reconcile these results. Downmodulation of IIS is thought to entail slower metabolism and cell growth, and thus lower rate of cell damage. The deregulation of nutrient sensing can be interpreted as an organismal survival response, which ultimately becomes deleterious with age. 

The principle of genetic determinism provides an appropriate underlying theory for research designs evaluating nutritional factors involved with lifespan. Nutritional studies are more accurately interpreted to have an impact on our understanding of longevity determination than aging [113].


Cellular senescence and phenotypic aging

A senescent cell stops dividing and features remarkable phenotypic changes, like the secretion of proinflammatory molecules [114]. Cell senescence is a crucial component of organismal development and is observed at every stage of life. It can be caused either by DNA damage (including telomere shortening), excessive mitogenic or oncogenic signaling, or the expression of a cell cycle inhibitor. Senescent cells accumulate in certain tissues with chronological aging [115]. Interestingly, senescence can be induced either by cellular endogenous pathways or by extra-cellular signaling pathways.

Two essential senescence pathways, activated in response to oncogenic alterations, have been identified : p16INK4a/Rb and p19ARF/p53 (3). The levels of tumor suppressor p16INK4a correlate with chronological age. p16INK4a and p19ARF are encoded by the same genetic locus (INK4a/ARF), which is associated with aging according to statistical studies.

Once again, there is disagreement over the effect of p16INK4a and p19ARF on lifespan. The activation of p53 (3) and INK4a/ARF could be regarded as a beneficial compensatory response to block the proliferation of damaged cells. However, when damage is pervasive, the regenerative capacity of tissues can be exhausted or saturated, and under these extreme conditions, the p53 and INK4a/ARF responses can accelerate aging.

Senescence might be a strategy to prevent a cell from proliferating into a tumoral cell. This anti-cancer system requires an efficient immune system to phagocyte senescent cells and robust stem cells to regenerate tissues. However, with chronological aging, senescent cells accumulate because of a slowdown of cell renewal and deteriorated immune mechanisms to clear senescent cells. Senescence is thus thought to promote early-life survival by preventing the development of cancer, but eventually to limit longevity as senescent cells accumulate. Deciding whether cellular senescence is a programmed aging mechanism needs further investigation : the link between cell senescence and phenotypic aging remains unclear.


Aging and exhaustion of stem cells

research-companies-human-longevity-and-life-span-Due to senescence of stem cells, aging tissues fail to regenerate as efficiently as younger tissues : they undergo fewer cell divisions. For instance, aging of hematopoietic stem cells entails a decrease in the production of adaptive immune cells and is thus involved in immunosenescence. Similar behaviours of stem cells are found in the brain, bone, and muscle fibers. DNA damage [116] and overexpression of proteins that inhibit cell cycle [117] could account for this behaviour.

Although adult stem cells express telomerase, they are not immune to telomere attrition [118] [119]. Accumulation of non-telomeric DNA damage and mutations has also been implicated in stem cell exhaustion [120] [121]. In the hematopoietic system, mutations that increase proliferation and survival are selected, and consistently, increased numbers of stem cells with pre-cancerous mutations are observed [122] [123] [124] [125]. DNA damage may also decrease stem cell numbers by causing them to undergo apoptosis or senescence.

Overexpression of sirtuin SIRT3 has been reported to enhance the regenerative capacity of old hematopoietic stem cells [126], suggesting sirtuins are also implicated in maintenance of stem cell function.

Stem cell exhaustion is suspected to play a prominent role in organismal aging, because it hampers cell renewal, an essential component of the aging process. Several hypotheses, described by Schultz and Sinclair in a 2016 review, try to explain how individual stem cells can function over the lifetime of an individual [127]. One of them is that stem cells use special mechanisms to prevent or reverse damage or epigenetic changes, including maintenance of long telomeres and enhanced proteostasis. Another hypothesis is that some stem cells decline with age while the healthiest are selected for. Models of improved stem cell function lead to improved tissue function consistently with what one would predict if stem cell aging is a crucial driver of tissue and organ aging [128] [129]. Understanding stem cell exhaustion has many implications for regenerative medicine.


A systemic approach of aging and lifespan determination

In 2014, by splicing animals together, scientists have shown that young blood can rejuvenate old tissues [130]. Moreover, lifespan-extending manipulations targeting one tissue can have beneficial consequences in other tissues [131] [132] [133]. These exciting results have triggered an active search for circulating systemic factors that could drive aging and coordinate the aging rate of different tissues and organs.

Age-related chronic inflammation

“Inflamm-aging” is a pro-inflammatory phenotype is observed in aging mammals [134]. Cytokines, the major players of the inflammatory response, allow communication between immune and somatic cells. Their chronic response might be partially responsible for frailty, development of age-related diseases, and functional decline [135] [136]. Multiple causes are examined : accumulation of proinflammatory tissue damage overtime, secretion of proinflammatory cytokines by senescent cells, dysfunctional immune system failing in efficiently clearing pathogens and dysfunctional host cells, mismanagement of apoptosis due to mitochondrial dysfunction, defective autophagy response and accumulation of damaged proteins triggering inflammatory response, change in the levels of hormones that regulate cytokine production (including testosterone), enhanced activation of NF-κB transcription factor.

These alterations result in an enhanced production of interleukin 1β (IL-1β), a tumor necrosis factor [101] [134] that induces the release of TNF-α. Interleukin-6 (IL-6) is released by TNF-α and IL-1β.

Nuclear factor-κB (NF-κB) is implicated in immune response and response to stress. It controls several genes associated with inflammation and is considered as a molecular culprit for inflammaging. The inhibition of NF-κB prevents age-associated features in different mouse models of accelerated aging [137] [138]. What is more, inhibiting NF-κB causes phenotypic rejuvenation of tissues [139]. Remarkably, SIRT-1 expression inhibits NF-κB.

Sirtuins could also influence inflammaging. Studies have revealed that, by deacetylating histones and components of inflammatory signaling pathways such as NF-κB, SIRT1 downregulates inflammation-related genes [140]. Reduction of SIRT-1 levels correlates with the development and progression of many inflammatory diseases, and pharmacological activation of SIRT1 may prevent inflammatory responses in mice [141] [142] [143]. SIRT-2 and 6 may downregulate the inflammatory response through deacetylation of NF-κB subunits and transcriptional repression of their target genes [60] [144].

Studies on the mRNA decay factor AUF-1 give in vivo evidence of the link between aging and inflammation. AUF1 directs cytokine mRNA degradation and participates in regulating the end of inflammatory response. AUF1-deficient mice feature a marked cellular senescence and premature aging phenotype. Interestingly, AUF1 also contributes to maintaining telomere length [145].

Once again, the age-associated inflammation can be interpreted as a defense mechanism that ultimately becomes deleterious overtime. Low levels of inflammatory response may be beneficial to tissue repair and regeneration by activating the immune system, but higher levels aggravate damage. Age-related inflammation could also severely undermine stem cell function [146].



Micro-RNAs (miRNAs) are a group of non-coding small RNAs. They can modulate gene expression by targeting mRNA with complementary sequence. Remarkably, miRNAs can modulate lifespan in invertebrates [147] [148] [149] by interacting with components of longevity networks or regulating stem cell regenerative abilities [150] [151] [152]. They could become an interesting biomarker of aging and age-related diseases, because miRNAs profiling reveals significant alterations in their expression levels [143].


Cell-free miRNAs have raised biologists’ attention because they might provide useful information for early diagnosis of cancer and other age-related diseases. Circulating miRNAs could be major systemic factors of aging. They are known to be involved in several aspects of the aging process :

  • Telomere length. miRNAs could be involved in the regulation of telomere length. Several miRNAs target mRNA implicated in telomere maintenance [153] ?? . Moreover, in humans, miRNA miR-138 is negatively correlated to telomerase reverse transcriptase (hTERT) levels [154].
  • Senescence. There is evidence that miRNAs modulating the expression of p53 and p21 regulate cellular senescence [155]. SIRT-1 could deacetylate p53 and modulate its activity. miR-34a is a p53-induced miRNA, which can regulate the expression level of SIRT-1 in mice [156]. The connection of SIRT-1, p53, and miR-34a could hint at a senescence-regulating circuit. Moreover, in stress-induced and oncogene-induced senescence models, p21 is found to be the target of multiple miRNAs [157] [158]. Remarkably, levels of miR-106b family are decreased in senescent cells. In particular, miR-106a targets p21 mRNA [159] and prevents cell senescence whether p53 is inhibited or not. Other members of the miR-106b family enhance cell cycle by targeting p21 [158] [160]. miRNAs are suspected to stand at the crossroads between senescence and age-related diseases.
  • Stem cell exhaustion. Some miRNAs regulate stem cell properties and could thus maintain cell-renewal capacity.
  • Inflammation. miRNAs could be involved in inflammation regulation through interactions with NF-κB [161] [162]. A relatively small number of miRNAs seem to be involved in regulating inflammation : their prototypes are miR-155, miR-21, and miR-146a [163] [164]. In physiological conditions, their transcription is at baseline levels, but pro-inflammatory signaling results in strong co-induction of their expression through a NF-κB-dependent mechanism [165].


Thymus atrophy and its role in immuno-senescence

The thymus is an organ supporting the development and differentiation of T immune cells. T-cells are crucial to the adaptive immune system, which enables the body to respond specifically to foreign invaders.

In the 1980s, Steinman demonstrated that thymic function gradually decreases from the first year of life [166] and that the thymus is atrophied during aging [167]. This involution results in decreased efficiency of T-cell development, and reduced emigration of na¨ıve Tcells [168]. The adaptative immune system thus declines while the innate immune system is reinforced.

As the immune system becomes less efficient with age, the incidence of diseases such as opportunistic infections, autoimmunity and cancer increases [169] [170] increases. According to M. R. Dowling and P. D. Hodgkin, this apparently detrimental behavior may have been selected for to optimize fighting infections and avoid reaction to self [171]. Age-associated decline in immune function would thus be an unfortunate side effect of this selective process.


The role of the hypothalamus

The hypothalamus communicates with multiple tissues through hormonal and neural networks. It coordinates metabolic and behavioral responses to nutritional and environmental stimuli in mammals. It could thus be a crucial actor of systemic aging and of longevity control [172].


Growth hormone (GH) releasing hormone and somatostatin, respectively stimulating and inhibiting GH release, are produced by hypothalamic neurons. The GH/IGF-1 pathway (regulating growth, metabolism and tissue repair) is well established to control longevity in mammals [173] (see “Nutrient sensing pathways”).

Inflammatory responses activate NF-κB in the hypothalamus, inducing a signaling pathway that results in reduced production of GnRH by neurons. The decline of this hormone could enhance numerous aging-related systemic changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis [174].

In 2013, Satoh et al. have demonstrated that brainspecific SIRT-1-overexpressing transgenic mice show lifespan extension. Excitingly, those mice exhibit phenotypes consistent with a delay in aging [175]. These phenotypes reveal enhanced neural activity, particularly in the dorsomedial and lateral hypothalamic nuclei. In this experiment, further information supported the longevity-promoting role of SIRT-1-mediated signaling in those areas of the hypothalamus. The findings of Satoh et al. suggest that SIRT-1 enhanced activity in the lateral and dorsomedail nuclei of the hypothalamus is crucial to in the systemic regulation of longevity in mammals.


Notes: Interesting components of aging pathways

(1) NAD

Nicotinamide adenine dinucleotide (NAD) is a coenzyme involved in many cell redox reactions, including ATP synthesis. It plays an essential role in many metabolic pathways, and is a substrate of both PARP proteins and sirtuins. Its oxidized form is known as NAD+, and its reduced form as NADH. NAD+ synthesis can occur either de novo from amino-acids, or by recycling preformed components. The cellular NAD+ pool could be depleted while aging [176]. This could be due to deterioration of synthesis pathways and/or enhanced degradation (possibly through PARP activation). NAD+ levels are thought to be a relevant molecular signature of aging. Precursors of NAD+ have been thoroughly studied because promoting the repletion of the NAD+ pool might activate sirtuins and help reverse aging.

(2) Sirtuins

Sirtuins are a family of NAD+-dependent proteins believed to be prominently implicated in the aging process. Sir2 was the first discovered sirtuin. In the 1990s, MIT Doctor Leonard Guarante found that sir2 gene controls longevity in yeast. Ortholog gene in C. Elegans proved crucial for longevity control too. Sirtuins are today thought to be key factors in longevity in many other species, including humans. Seven of them have been identified in mammals [177]. They have an enzymatic activity and can induce changes in cell metabolism and physiology. SIRT-1, 6 and 7 are nuclear proteins, they epigenetically influence gene expression by deacetylating histones [178]. SIRT-2 is involved in cell cycle control [178]. SIRT-3 and 5 regulate metabolic enzymes in the mitochondria [178]. They are believed to be involved in body response to calorie restriction.

(3) p53

p53 is a tumor suppressor known for its involvement in anti-cancer mechanism. It can activate DNA repair proteins and initiate apoptosis or senescence in response to DNA damage. Overexpression of p53 is deleterious because it drives excessive apoptosis and senescence [179]. p53 can either inhibit or stimulate autophagy depending on stress conditions [180] [181]. It might also affect aging and metabolism through its implication in mitochondrial function [182]. p53 protein DNA binding and transcriptional activity increases with age. p53 has an ambiguous role in the aging process, but it seems like it regulates an essential balance between aging and tumor suppression [183].

(4) Mitochondria

Mitochondria are cellular organelles that generate most of the cell’s adenosine triphosphate (ATP), used as a source of chemical energy. Oxidative phosphorylation (OXPHOS) is the metabolic pathway in which cells use enzymes to oxidize nutrients, releasing energy which is used to reform ATP. It takes place inside the mitochondria. Sirtuins are known to play a major role in mitochondrial activity regulation [178] [185]. Mitophagy is the deletion of mitochondria through autophagy. It happens as a response to damage or stress. Defective mitophagy (see ”Loss of proteostasis”) has been identified as a key factor for mitochondrial dysfunction [186].

(5) Autophagy

Autophagy is a regulated pathway responsible for the lysosomal degradation of cytoplasmic organelles or cytosolic components [181]. Autophagy activity decreases with age [72] [184], but is upregulated in response to calorie restrictions [71]. This upregulation can be interpreted as an effort to raise energy supplies when nutrients are scarce. Autophagy disruption is a key component of cellular aging, linked to mitochondrial dysfunction and loss of proteostasis.

(6) PGC-1α and HIF-1α

Activity of PGC-1α and HIF-1α can be modulated by sirtuins [187] [188]. Transcription factor PGC-1α directs a metabolic response that includes mitochondriogenesis, enhanced antioxidant defenses, and improved fatty acid oxidation [189]. HIF-1α is a subunit of transcription factor HIF-1. HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals. It is involved in cell proliferation and survival and response to hypoxia [190]. HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism [191]. Gomes et al. have hypothesized that AMPK acts a switch between PGC-1α– dependent and HIF-1α-dependent regulation of mitochondria by sirtuins [93].

(7) Calorie restrictions

Calorie restrictions (CR) have been known to extend longevity in a variety of species, including mammals, since the 1930s. They are believed to favor mitochondrial oxidative metabolism and stress tolerance [177]. Studies tend to show that the lifespan-extending effect of CR depends on sirtuins [192] [193]. The evolution theory can bring an interesting insight into these mechanisms. When the energy supply in the environment is scarce, the metabolism switches to an energy-efficient mode. The aim is to ensure survival to be alive when the environment becomes more favorable to reproduction.



Written by Delphine Vendryes under the supervision of Guilhem Velve Casquillas and Christophe Pannetier. For more information regarding this subject, please contact us. 

We are willing to launch research projects on anti-aging, so if you are keen in this topic and you are interested in collaboraing with us, please contact us.



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