David Gems

Autophagy is proposed to protect against aging by clearing damaged cellular constituents. In line with this several life-extending interventions in model organisms show some degree of autophagy dependence. In C. elegans, inhibiting autophagy can shorten, lengthen or have no effect on lifespan. Differences between published findings likely reflect variability in experimental conditions. Here we investigate the condition dependence of effects on lifespan of RNA-mediated interference (RNAi) knockdown of autophagy pathway components. Effects on interventions causing a strong Age (increased lifespan) phenotype were examined, mainly mutation of daf-2 (insulin/IGF-1 receptor). Factors varied included daf-2 mutant allele class, atg gene and temperature. Effects on lifespan of atg RNAi proved to be highly condition dependent. Notably, for most atg genes tested lifespan was not usually reduced more in the long-lived mutant than in the wild-type control. Greater suppression was seen at 20°C for certain atg genes with daf-2(e1368) but not daf-2(e1370). At 25°C, little reduction in lifespan was seen. However, atg-18 knockdown behaved differently, suppressing daf-2 Age under all conditions, suggesting possible pleiotropic action. Condition dependent effects were also seen with respect to glp-1 (reduced germline development) Age. Furthermore, presence of 5-fluoro-2’-deoxyuridine (FUDR) at a high concentration caused knockdown of several atg genes to increase lifespan in wild-type C. elegans. Thus, depending on experimental conditions, atg knockdown can increase, decrease or have no effect on daf-2 Age. The lack of suppression of daf-2 Age by atg RNAi under most conditions questions the importance of autophagy for this phenotype. Moreover, condition dependence of effects creates a risk of possible condition selection bias.

What is the ultimate goal of biogerontology (the study of the biology of aging)? A fashionable answer these days, often encountered, is that it is to extend healthspan not lifespan. Here we argue that this is a misguided cliché. Experimental research with animal models has demonstrated the possibility of intervening in and retarding the aging process, and extending lifespan. This, to varying degrees, increases both healthspan and gerospan, the later-life phase in diminished health. Considering possible equivalent interventions in human aging it would of course be desirable to maximize the former and minimize the latter. However, should a given intervention extend gerospan, given that it would postpone death (i.e., save lives) it would, in many circumstances, be unethical to withhold it. Life in moderately diminished health is generally preferable to death, and this is reflected in the recognized value of many life-saving medical interventions that do not restore full health. Thus, “extending healthspan but not lifespan” is not a coherent objective for research on aging.

Autophagy is proposed to protect against aging by clearing damaged cellular constituents. In line with this several life-extending interventions in model organisms show some degree of autophagy dependence. In C. elegans, inhibiting autophagy can shorten, lengthen or have no effect on lifespan. Differences between published findings likely reflect variability in experimental conditions. Here we investigate the condition dependence of effects on lifespan of RNA-mediated interference (RNAi) knockdown of autophagy pathway components. Effects on interventions causing a strong Age (increased lifespan) phenotype were examined: mainly mutation of daf-2 (insulin/IGF-1 receptor), but also suppression of germline development by mutation of glp-1. Factors varied included daf-2 mutant allele class, atg gene, temperature and presence of 5-fluoro-2’-deoxyuridine (FUDR). Effects on lifespan of atg RNAi proved to be highly condition dependent. Notably, for most atg genes tested lifespan was not usually reduced more in the long-lived mutant than in the wild-type control. Greater suppression was seen at 20°C for certain atg genes with daf-2(e1368) but not daf-2(e1370). At 25°C, little reduction in lifespan was seen. However, atg-18 knockdown behaved differently, suppressing daf-2 Age under all conditions, suggesting possible pleiotropic action. In wild-type C. elegans, FUDR at a high concentration caused knockdown of several atg genes to increase lifespan. Thus, depending on experimental conditions, atg knockdown can increase, decrease or have no effect on daf-2 Age. Condition dependent effects were also seen with respect to glp-1 Age. The lack of suppression of daf-2 Age by atg RNAi under most conditions questions the importance of autophagy for this phenotype. Moreover, condition dependence of effects creates a risk of possible condition selection bias.

Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans . However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover, life-extension by IIS reduction is particularly inter-individually variable within populations, confounding efforts to understand the intra-individual biology of such interventions. Here, we performed a longitudinal investigation at individual nematode resolution, of IIS reduction on aging-related health and lifespan, through temporally-controlled auxin-induced degradation (AID) of the DAF-2 insulin/IGF-1 receptor. Our results show how inter-individual variation in aging rate within control populations explains the complex demographic effects of age-specific DAF-2 AID on population lifespan. Strikingly, adult-limited IIS reduction causes an inter-individually homogeneous increase in lifespan (reducing Gompertz α rather than β ) that is driven by healthspan expansion and compression of morbidity. Unexpectedly, cessation of DAF-2 AID in decrepit elderly individuals rejuvenates locomotory capacity and extends lifespan, showing that higher levels of IIS are optimal for health and survival towards the end of life. We also document a memory effect of transient IIS reduction during early adulthood, that is sufficient to fully extend lifespan (+189% median lifespan). Together, these findings demonstrate that both lifespan and healthspan can be maximized by appropriate temporal and directional modulation of IIS.

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β , respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality. Here, we investigate the biological basis of α and β using the nematode Caenorhabditis elegans , through the combined study in populations and individuals of effects of life-extending interventions on mortality and age-changes in health. We demonstrate that reductions in β arise not from slowed biological ageing, but rather from expansion of decrepitude (gerospan) in longer-lived population members. In contrast, reductions in α better reflect healthspan expansion, an indicator of slowed biological ageing. Thus, our investigation presents a new, empirical understanding of the Gompertz parameters that inverts their traditional interpretations.

Dietary restriction (DR) extends lifespan in many animal species. In C. elegans , Eat mutants with pharyngeal defects that impair feeding exhibit reduced growth rate and fertility and are typically long-lived, suggesting a DR effect. We report that Eat mutant longevity is largely or wholly a consequence of suppression of feeding activity-dependent infection of the pharynx by their E. coli food source. eat-2 mutants, widely used as a DR model, were among only 2/8 Eat mutants tested whose longevity were to any degree independent of bacterial infection. Moreover, among Eat mutants, phenotypic indicators of reduced nutrition correlated with one another, yet not with longevity. Thus, eat-2 longevity is partially due to infection resistance rather than DR, and residual, infection-independent longevity could equally reflect DR or some other consequence of their cholinergic signaling defect. We therefore conclude that eat-2 mutants are not at present a trustworthy model for studies of DR.

Interventions that extend lifespan in animal models could, in principle, decelerate the aging process as a whole. Alternatively, they could act by suppressing one or more individual late-life pathologies that contribute to mortality. Here we show how, in the nematode Caenorhabditis elegans , late-life pathologies can compete in a hierarchical fashion to cause death, such that removal of one cause of death can unmask another. Under standard culture conditions, a major cause of death in elderly C. elegans is infection by their bacterial food source. We report that only when such infection is prevented is lifespan extended by suppression of a second senescent pathology, teratoma-like uterine tumors. Thus, as in mammals, lifespan in wild-type C. elegans can be limited by naturally-occurring neoplasia. By contrast, blocking bacterial infection attenuated the life-shortening effects of vitellogenesis, and did not unmask a life-shortening effect of distal gonad degeneration. Thus, depending on the masking or unmasking of competing causes of mortality in the hierarchy of causes of death, nematode lifespan limitation in different contexts can reflect action of distinct life-limiting senescent pathologies. This underscores how increases in lifespan do not necessarily reflect a reduction in overall aging rate.

As global human life expectancy continues to rise, accompanying increases in healthspan that prevent morbidity expansion become increasingly imperative. Population lifespan can increase in distinct ways, for instance through rectangularization (steepening) or triangularization (flattening) of survival curves. These two demographic changes, particularly rectangularization, occur frequently across human and model organism populations, yet their biological determinants and effects on healthspan and morbidity are largely unknown. Notably, these modes of life-extension occur when parameters of the Gompertz mortality model (capturing exponential age-increases in mortality rate) change inversely, a widely-reported phenomenon known as the Strehler-Mildvan correlation – whose biological basis also remains unexplained. We therefore investigated longitudinal health, morbidity and lifespan in 30 Caenorhabditis elegans cohorts using multiple life-extension protocols. We report that survival curve rectangularization results from healthspan expansion in short-lived population members, whereas triangularization (which primarily extends the curve tail) from healthspan and morbidity expansion in long-lived population members. Interestingly, rectangularization and triangularization respectively decrease and increase inter-individual variation in the aging process, and the mode of life-extension that occurs depends on levels of existing variation. Notably, triangularization was more effective at extending lifespan without morbidity expansion. Analysis of fruit fly and mouse data show that these biodemographic dynamics are also largely evolutionarily conserved.

Aging (senescence) is characterized by development of diverse senescent pathologies and diseases, leading eventually to death. The major diseases of aging, including cardiovascular disease, cancer and chronic obstructive pulmonary disease (COPD), are multifactorial disorders, resulting from complex interactions between multiple etiologies. Here we propose a general account of how different determinants of aging can interact to generate late-life disease. This account, initially drawn from studies of the nematode Caenorhabditis elegans, depicts senescence as the product of a two-stage process. The first stage involves the diverse causes of disease prior to aging, that cause disruption of normal biological function. These include infection, mechanical injury and mutation (somatic and inherited). Second, etiologies largely confined to aging: deleterious, late-life consequences of evolved wild-type gene action, including antagonistic pleiotropy. Prior to aging, diverse insults lead to accumulation of various forms of injury that is largely contained, preventing progression to major pathology. In later life, wild-type gene action causes loss of containment of latent disruptions, which form foci for pathology development. Pathologies discussed here include osteoarthritis, cancer, late-life recrudescence of infection, and consequences of late-acting deleterious mutations. Such latent injury foci are analogous to seeds which in later life, in the context of programmatic senescent changes, germinate and develop into disease.

Aging leads to age-related pathology that causes death, and genes affect lifespan by determining such pathology. Here we investigate how age-related pathology mediates the effect of genetic and environmental interventions on lifespan in C. elegans by means of a data-driven approach employing machine learning (ML). To this end, extensive data on how diverse determinants of lifespan (sex, nutrition, genotype, mean lifespan range: 7.5 to 40 days) affect patterns of age-related pathology was gathered. This revealed that different life-extending treatments result in distinct patterns of suppression of senescent pathology. By analysing the differential effects on mid-life pathology levels and lifespan, the ML models developed were able to predict lifespan variation, explaining 79% of the variance. Levels of pathology in the pharynx and intestine proved to be the strongest predictors of lifespan. This suggests that elderly C. elegans die predominantly from late-life disease affecting these organs. In addition, we noted profound sex differences in age-related pathology: the striking age-related pathologies in hermaphrodites affecting organs linked to reproduction are absent from males, suggesting that reproductive death may be hermaphrodite limited.