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. Author manuscript; available in PMC: 2019 Jul 1.
Published in final edited form as: Exp Gerontol. 2017 Aug 7;107:136–139. doi: 10.1016/j.exger.2017.08.005

Mechanisms underlying longevity: A genetic switch model of aging

Jeremy M Van Raamsdonk 1,2,3
PMCID: PMC5803475  NIHMSID: NIHMS899351  PMID: 28797825

Abstract

While the questions of “What causes aging?” and “Why do we age?” and “How can we stop it?” remain unanswered, recent advances in aging research have continued to increase our understanding of the aging process. Until the last couple of decades, aging was viewed as an inevitable process of damage accumulation and not a subject for scientific pursuit. This view changed when it was demonstrated that the aging process is in fact malleable and genetically determined: mutations in single genes can have dramatic effects on longevity. Despite the rapid advancement of our knowledge about aging, the cause of aging remains unclear. In this paper, experiments demonstrating the roles of genetics and epigenetics in modulating longevity are reviewed, concluding with a new model of aging. This genetic switch model of aging proposes that aging is caused by a genetically-programmed turning off of survival and maintenance pathways after reproduction finishes leading to a progressive functional decline. If this model is correct, it may be possible to extend lifespan and healthspan by identifying the molecular pathways involved and simply turning the switch back on.

Keywords: Aging, genetics, epigenetics, lifespan, theory

One of the major questions in aging research is “what causes aging?” Despite many advances and years of investigation, the answer to this question remains poorly defined. Nonetheless, a number of theories have been proposed. A group of theories, collectively known as damage accumulation hypotheses, suggest that aging is caused by the accumulation of damage with increasing age. The most widely accepted of these theories is the free radical theory of aging (FRTA). The FRTA proposes that reactive oxygen species (ROS) generated by normal metabolism cause oxidative damage that accumulates with age eventually leading to cellular dysfunction, thereby causing aging (Harman 1956). While it is clear that oxidative damage increases with advancing age, and that high levels of ROS can be toxic, accumulating evidence indicates that oxidative damage can be experimentally dissociated from lifespan (Van Raamsdonk and Hekimi 2010). It has been shown that increasing oxidative damage does not necessarily decrease lifespan (Yang and others 2007) and that having increased oxidative damage is compatible with long life (Van Raamsdonk and Hekimi 2009). In fact, ROS have been shown to act as signaling molecules (Schieber and Chandel 2014; Shadel and Horvath 2015) and mild increases in ROS in the right place and at the right time can increase lifespan (Schaar and others 2015). For example, an increase in ROS has been shown to modify a cysteine residue within IRE-1 kinase, which leads to activation of the SKN-1/NRF2 antioxidant response, and extended longevity (Hourihan and others 2016). These results suggest that while the accumulation of damage is associated with increased age, it does not cause aging. Moreover, it casts doubt on the FRTA, suggesting the possibility that new theories of aging are needed. In this paper, I review some important experiments on the genetics and epigenetics of aging, and conclude by proposing a new theory of what causes aging.

Longevity is a genetically encoded trait

While aging has traditionally been thought of as a stochastic process of damage accumulation, work from the past three decades has demonstrated that aging is a malleable process that can be strongly influenced by genetics. Using the worm C. elegans, experiments in the late 1980s and early 1990s demonstrated that mutations in single genes can markedly increase the lifespan of the organism (Friedman and Johnson 1988; Kenyon and others 1993; Wong and others 1995)). In fact, it has been shown that changing just one gene out of 20,000 genes in the worm genome can result in an amazing tenfold increase in lifespan from 20 days to over 200 days (Ayyadevara and others 2008). Mutations in single genes have also been shown to increase lifespan in other models organisms, including yeast, flies and mice. Importantly, many of the genes that modulate longevity appear to be conserved across species (Bitto and others 2015) and genetic variation in at least some of these genes has been shown to be associated with longevity in humans (e.g. (Suh and others 2008)). At present there have been 270, 570, 108, and 50 life-extending genes identified in yeast, worms, flies and mice, respectively ((Tacutu and others 2013); http://genomics.senescence.info/genes/). While the functions of many of these genes, and their role in determining lifespan, have yet to be defined, the identification of these longevity-modulating genes has permitted the delineation of multiple pathways of lifespan extension, such as the insulin-IGF1 signaling pathway, the dietary restriction pathway, and the mild mitochondrial impairment pathway. The fact that single gene mutations can increase lifespan clearly indicates that organisms have the genetic capacity to live longer.

Interventions in adult and aged animals can increase lifespan

After it had been established that genetic pathways can modulate longevity, a key question was to determine when these pathways act to extend lifespan. It was shown that timing requirements for distinct pathways of lifespan extension were different. Decreasing insulin/IGF-1 signaling has been shown to double the lifespan of the worm (Friedman and Johnson 1988; Kenyon and others 1993). To determine when decreasing insulin/IGF-1 signaling could increase lifespan, Dillin et al. used RNAi to knockdown the expression of the insulin/IGF-1 receptor gene daf-2 during development only or beginning at different developmental stages and continuing to death (Dillin and others 2002a). It was found that decreasing daf-2 expression during development had no effect on lifespan, while decreasing expression throughout adulthood could increase lifespan even if the treatment was begun as late as day 6 of adulthood. This indicates that decreasing insulin-IGF1 signaling acts during adulthood to increase lifespan, and more generally demonstrates that changes taking place in adult organisms can still increase lifespan. As a dramatic example of this, it was shown that treating 600 day old mice with the mTOR inhibitor rapamycin could still significantly increase their lifespan (Harrison and others 2009). It was subsequently shown that rapamycin could be delivered for just 3 months in 2 year old mice and extend longevity (Bitto and others 2016). Similarly, it has been shown that methionine restriction beginning at 1 year of age is sufficient to increase lifespan in mice (Sun and others 2009). In addition, parabiosis experiments, in which the vasculature of an old mouse is connected to a young mouse, have shown that specific circulating factors from young mice are able to increase the lifespan of old mice (Katsimpardi and others 2014; Sinha and others 2014; Villeda and others 2014). Finally, it has been shown that exposing worms to a mild heat stress for just 2 hours during the first week of adulthood is sufficient to increase their lifespan by 5–10 days (Dues and others 2016; Lithgow and others 1995). Combined, these results show that the lifespan of an organism is still malleable during adulthood as interventions administered throughout adulthood, or for short periods of adulthood, can increase lifespan.

Changes during development can affect adult lifespan

Intriguingly, some pathways of lifespan extension affect longevity exclusively during development. It has been shown that mutations (Feng and others 2001; Lakowski and Hekimi 1996; Yang and Hekimi 2010) and RNAi knockdowns (Lee and others 2003) that mildly affect mitochondrial function cause increased lifespan. To determine whether there is a critical window of time for decreasing mitochondrial function to increase lifespan, Dillin et al. used RNAi to knock down subunits of the electron transport chain (ETC) during development only or during adulthood only. They found that decreasing mitochondrial function during development was sufficient to increase lifespan to the same extent as decreasing function throughout development and adulthood, while knocking down the expression of genes encoding subunits of the ETC during adulthood had no effect on lifespan (Dillin and others 2002b). The fact that maternal expression of CLK-1 is sufficient to revert the lifespan of a homozygous clk-1 deletion mutant to wild-type also suggests that inhibiting mitochondrial function increases lifespan during development (Wong and others 1995). The ability of interventions during development to increase adult lifespan is not limited to worms. In mice, it has been shown that decreasing nutrition intake during the first 20 days of life (until weaning) by increasing litter size by 50% (crowded litter) is sufficient to increase mean and maximum lifespan by 100 days (Sun and others 2009). These results show that interventions administered during development can be sufficient to increase lifespan.

Epigenetic changes can extend longevity

Since lifespan can be modulated through changes in gene expression, and interventions administered during development can increase adult lifespan, it is plausible that these interventions induce epigenetic modifications that maintain changes in gene expression throughout adulthood. To determine the extent to which epigenetic modifications could affect longevity, Greer et al. performed a targeted RNAi screen in C. elegans of known modifiers of histone methylation (Greer and others 2010). They found that knocking down expression of multiple members of a H3K4 trimethylation complex resulted in increased lifespan. Intriguingly, they went on to show that deficiencies in the trimethylation complex in the parental generation resulted in increased lifespan in genetically wild-type (+/+) offspring not only in the first generation of progeny but for the first four generations of progeny (Greer and others 2011). The fact that overexpression of the histone deacetylase SIRT6 in mice increases lifespan demonstrates that epigenetic modifications can also influence longevity in mammals (Kanfi and others 2012). Further support for this conclusions comes from the finding that the epigenetic changes induced by cellular reprogramming towards pluripotency increase lifespan in a progeria mouse model (Ocampo and others 2016). A role for epigenetics in determining lifespan is further supported by observations that biologic age can be estimated using measurements of DNA methylation (cytosine-5 methylation within CpG dinucleotides) in what is known as the epigenetic clock (Horvath 2013). These results indicate that epigenetic changes can lead to extended longevity.

Decline in stress resistance with age can be mediated by epigenetic modifications

As the ability to resist multiple stresses has been proposed to be a key determinant of longevity (Miller 2009), a number of groups have explored the relationship between stress resistance and aging. In every case, it was found that resistance to stress declines with age (Bansal and others 2015; Dues and others 2016; Labbadia and Morimoto 2015). In these experiments performed in C. elegans, the precise timing of the decrease in stress resistance varied somewhat between labs but it was generally observed that stress resistance declined shortly after the peak reproductive period (day 1–3 of adulthood). This suggests that worms maintain their ability to respond to stress until they have successfully passed on their genes to the next generation. Consistent with this conclusion, it was observed that the ability of multiple stress response pathways to be activated by stress is lost with advancing age (Dues, Andrews et al. 2016).

In exploring the mechanism involved in the decline of one of these stress response pathways (the heat shock response), it was found that the decrease in stress resistance is a genetically-programmed event (Labbadia and Morimoto 2015). In young adult worms, the H3K27me3 demethylase JMJD-3.1 removes methyl groups from H3K27 thereby allowing the heat shock transcription factor HSF-1 to bind to heat shock elements (HSE) to activate genes involved in the heat shock response. After the peak reproductive period, the expression of JMJD-3.1 decreases, resulting in a failure to demethylate H3K27 surrounding HSEs, thereby blocking the binding of HSF-1 and preventing the upregulation of genes involved in the heat shock response. While the cause of decreased JMJD-3.1 expression has not yet been determined, this indicates that the ability to respond to stress is essentially turned off after reproduction. Interestingly, overexpression of JMJD-3.1 was found to be sufficient to increase both thermotolerance and lifespan (Labbadia and Morimoto 2015).

Epigenetic modifications contribute to increased lifespan resulting from mild mitochondrial impairment

The histone demethylase JMJD-3.1 was also shown to mediate the lifespan increase caused by mutations and RNAi that affects the mitochondrial ETC. In an RNAi screen for genes required for mild impairment of mitochondrial function to increase lifespan, it was found that two histone demethylases, JMJD-3.1 and JMJD-1.2, are required for the long lifespan of cco-1 RNAi treated worms and isp-1 mutants (Merkwirth and others 2016). In this work, they also showed that overexpression of either of these histone demethylases is sufficient to increase lifespan. In a related study, it was shown that the H3K9 methyltransferase MET-2 is also required for the long lifespan of worms with mildly impaired mitochondrial function (Tian and others 2016). Knocking down cco-1 using RNAi was shown to induce changes in chromatin structure, numerous changes in gene expression, including the activation of the mitoUPR, and increased lifespan, all of which are prevented in by disruption of met-2. Combined, these studies provide mechanistic insight into how lifespan can be modulated by epigenetic modifications.

Genetic Switch Model of Aging

Based on the findings outlined above, I would like to propose a new model for aging. The model suggests that aging is caused by a genetically-programmed switch in which organisms turn off genetic pathways required for repair, maintenance, stress resistance and homeostasis leading to the functional decline that causes aging (Fig. 1). In young organisms, these pathways respond to any damage or stresses that occur, thereby keeping the organism in a youthful state. At some point in time, during or after reproduction, these survival pathways are switched off (or turned down). This could be a single switch controlling multiple pathways, or multiple switches. Once these pathways are turned off, the organism no longer repairs all damage, exhibits a decreased ability to respond to stress, and does not maintain homeostasis. As a result, the youthful state of the organisms is lost, the organism’s susceptibility to disease increases and the chance of death rises – the organism ages.

Figure 1. Genetic switch model of aging.

Figure 1

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In young organisms energy is invested into repair, maintenance, stress resistance and homeostasis pathways. This keeps the organism in a youthful state with low risk of disease and death by internal causes. At some point during or after reproduction a genetic switch, or switches, occurs in which the repair, maintenance, stress resistance and homeostasis pathways are turned off, or turned down, even though these pathways are still able to function optimally. The genetic switch may also trigger a redistribution of resources from somatic maintenance to reproduction. The decline resulting from the loss of these survival pathways increases susceptibility to disease and the chance of death, thereby causing aging.

How might the genetic switch be mediated?

Just as specific genes are turned on or off at precise times during embryonic and early development, genes controlling repair, maintenance, stress resistance and homeostasis, may be turned off at distinct times during later development (aging). Lasting changes in gene expression could be maintained through epigenetic modifications and changes in chromatin structure.

Why might an organism turn off repair, maintenance, stress resistance and homeostasis genes?

It is clear from the experiments described above that organisms have the genetic capacity to live longer. From an evolutionary perspective, the goal of an organism is to pass on its genes and to promote the survival of its progeny such that their genes continue to survive. With this view in mind, it could be seen to be advantageous for organisms to turn off repair, maintenance, stress resistance and homeostasis pathways after reproduction is finished, or after that organism has finished promoting the survival of its offspring. Turning off repair, maintenance, stress resistance and homeostasis pathways would lead to a functional decline and make the organism more susceptible to disease and death. In this way, the organism would reduce the amount of time that it is competing with its offspring for resources thereby increasing the chance that the offspring will pass on its genes to the next generation. In addition, the resources that were previously invested into somatic maintenance could be redistributed to support reproduction, again favoring the survival of the progeny over the parent.

Can the genetic switch be turned back on?

Since organisms have the genetic capacity to live longer, it is plausible that the genetic switch could be turned back on to extend lifespan and healthspan. From the experiments described above, it is clear that interventions administered during adulthood can still increase lifespan (rapamycin, dietary restriction, metformin, parabiosis, heat shock). As the molecular pathways controlling longevity continue to be elucidated, our increased understanding of the aging process may permit us to target specific molecules to extend lifespan. For example, in the experiments described above in which the expression of the histone demethylase JMJD-3.1 declines with age, strategies to maintain the expression of this protein throughout adulthood may preserve an organism’s ability to response to stress and extend their longevity.

How does this theory fit with other theories of aging?

The idea that evolution acts primarily before reproduction occurs is also a key component of other established theories of aging. The antagonistic pleiotropy theory proposes that because selective pressure is much greater prior to reproduction that genes with a small beneficial effect before reproduction that cause a significant decline after reproduction would not be selected against by evolution and would therefore be allowed to accumulate (Williams 1957). The hyperfunction theory of aging is similar in that it suggests that genes that are beneficial during development or reproduction are simply left on after reproduction is complete leading to detrimental effects due to excessive accumulation of unneeded gene products (Blagosklonny 2012; Gems and de la Guardia 2013). This theory would suggest the possibility that another aspect of the genetic switch model might be that genes that should be switched off following reproduction are not. Combined with the switching off of protective pathways this could contribute to a further acceleration of the aging process.

What are considerations for other species?

Different organisms vary in their reproductive strategies including the amount of time spent nurturing offspring. While some organisms, including C. elegans, produce large numbers of progeny and expend little or no effort in raising their offspring, other organisms, including humans, have few progeny and invest a significant amount of resources in nurturing their young in order to improve their chances of survival. In organisms that do not nurture their young, there would be a selective advantage to an abrupt switch followed by a rapid decline. In contrast, for those organisms that do care for their young, a delayed switch or progressive decline would be more advantageous for the survival of their offspring.

Conclusions

Since the discovery that single genes can affect longevity, research aimed at understanding the aging process has identified a number of genetic pathways that modulate lifespan. Nonetheless, it is still unclear what causes aging. In this paper, I propose that aging is caused by a genetically-programmed turning off of survival and maintenance pathways. Since organisms have the capacity to live longer, it may be possible to extend lifespan and healthspan by keeping these pathways active during adulthood.

Highlights.

  • Lifespan is a malleable trait

  • Genes have a strong influence on lifespan

  • Epigenetic modifications can extend longevity

  • Proposes the genetic switch model of aging

Acknowledgments

I would like to thank Megan Senchuk for carefully reviewing this manuscript and providing suggestions for improvement. This work was supported by the National Institutes of General Medical Sciences (R01 GM121756, PI: Jeremy Van Raamsdonk) and the Van Andel Research Institute.

Footnotes

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