Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings

Growth hormone deficiency or resistance resulting from spontaneous or experimentally produced mutations in laboratory mice delay aging and increase lifespan. Alterations in insulin-like growth factor-1 (IGF-1) and insulin signaling emerged as likely mechanisms linking growth hormone and aging, and increased longevity was reported in mice with selective deletion of IGF-1 receptor in all tissues or insulin receptor in fat. Recent studies in mice with reduced IGF-1 levels or deletion of pregnancy-associated plasma protein-A, a protease that cleaves one of the IGF-1 binding proteins, strongly support the role of IGF-1 in the control of longevity. Reports of increased lifespan in mice with deletion of insulin receptor substrate (IRS) 1, reduced expression of IRS2, or selective deletion of IRS2 in the brain specifically implicate the IRS-PI3K-Akt-Foxo signaling pathway (which is shared by IGF-1 and insulin) in the control of aging. These important novel findings also strengthen the evidence for evolutionary conservation of mechanisms regulating lifespan in worms, insects and mammals.     

Genetic and pharmacological factors that influence reproductive aging in nematodes

Age-related degenerative changes in the reproductive system are an important aspect of aging, because reproductive success is the major determinant of evolutionary fitness. Caenorhabditis elegans is a prominent organism for studies of somatic aging, since many factors that extend adult lifespan have been identified. However, mechanisms that control reproductive aging in nematodes or other animals are not well characterized. To use C. elegans to measure reproductive aging, we analyzed mated hermaphrodites that do not become sperm depleted and monitored the duration and level of progeny production. Mated hermaphrodites display a decline of progeny production that culminates in reproductive cessation before the end of the lifespan, demonstrating that hermaphrodites undergo reproductive aging. To identify factors that influence reproductive aging, we analyzed genetic, environmental, and pharmacological factors that extend lifespan. Dietary restriction and reduced insulin/insulin-like growth factor signaling delayed reproductive aging, indicating that nutritional status and a signaling pathway that responds to environmental stress influence reproductive aging. Cold temperature delayed reproductive aging. The anticonvulsant medicine ethosuximide, which affects neural activity, delayed reproductive aging, indicating that neural activity can influence reproductive aging. Some of these factors decrease early progeny production, but there is no consistent relationship between early progeny production and reproductive aging in strains with an extended lifespan. To directly examine the effects of early progeny production on reproductive aging, we used sperm availability to modulate the level of early reproduction. Early progeny production neither accelerated nor delayed reproductive aging, indicating that reproductive aging is not controlled by use-dependent mechanisms. The implications of these findings for evolutionary theories of aging are discussed.     

Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan

Much excitement has arisen from the observation that decrements in insulin‐like signaling can dramatically extend lifespan in the nematode, Caenorhabditis elegans, and fruitfly, Drosophila melanogaster. In addition, there are tantalizing hints that the IGF‐I pathway in mice may have similar effects. In addition to dramatic effects on lifespan, invertebrate insulin‐like signaling also promotes changes in stress resistance, metabolism and development. Which, if any, of the various phenotypes of insulin pathway mutants are relevant to longevity? What are the genes that function in collaboration with insulin to prolong lifespan? These questions are at the heart of current research in C. elegans longevity. Two main theories exist as to the mechanism behind insulin's effects on invertebrate longevity. One theory is that insulin programs metabolic parameters that prolong or reduce lifespan. The other theory is that insulin determines the cell's ability to endure oxidative stress from respiration, thereby determining the rate of aging. However, these mechanisms are not mutually exclusive and several studies seem to support a role for both. Here, we review recently published reports investigating the mechanisms behind insulin's dramatic effect on longevity. We also spotlight several C. elegans genes that are now known to interact with insulin signaling to determine lifespan. These insights into pathways affecting invertebrate lifespan may provide a basis for developing strategies for pharmacological manipulation of human lifespan.     

Evidence for a genetic basis of aging in two wild vertebrate populations

Aging, or senescence, defined as a decline in physiological function with age, has long been a focus of research interest for evolutionary biologists. How has natural selection failed to remove genetic effects responsible for such reduced fitness among older individuals? Current evolutionary theory explains this phenomenon by showing that, as a result of the risk of death from environmental causes that individuals experience, the force of selection inevitably weakens with age. This in turn means that genetic mutations having detrimental effects that are only felt late in life might persist in a population. Although widely accepted, this theory rests on the assumption that there is genetic variation for aging in natural systems, or (equivalently), that genotype-by-age interactions (GxA) occur for fitness. To date, empirical support for this assumption has come almost entirely from laboratory studies on invertebrate systems, most notably Drosophila and C. elegans, whereas tests of genetic variation for aging are largely lacking from natural populations. By using data from two wild mammal populations, we perform quantitative genetic analyses of fitness and provide the first evidence for a genetic basis of senescence to come from a study in the natural environment. We find evidence that genetic differences among individuals cause variation in their rates of aging and that additive genetic variance for fitness increases with age, as predicted by the evolutionary theory of senescence.     

DO‐SRS imaging of diet regulated metabolic activities in Drosophila during aging processes

Lipid metabolism plays crucial roles during aging processes, but how it is regulated by diets and how it interplays with aging still remain unclear. We proposed a new optical imaging platform by integrating heavy water (D₂O) probing with stimulated Raman scattering (DO‐SRS) microscopy, for the first time, to directly visualize and quantify lipid metabolism regulated by different diets and insulin signaling pathway in Drosophila fat body during aging. We found that calorie restriction, low protein diet, and (moderately) high protein and high sucrose diets enhanced lipid turnover in flies at all ages, while (moderately) high fructose and glucose diets only promoted lipid turnover in aged flies. The measured lipid turnover enhancements under diverse diets were due to different mechanisms. High protein diet shortened the lifespan while all other diets extended the lifespan. Downregulating the insulin signaling pathway enhanced lipid turnover, which is likely related to lifespan increase, while upregulating insulin signaling pathway decreased lipid turnover that would shorten the lifespan. Our study offers the first approach to directly visualize spatiotemporal alterations of lipid turnover in aging Drosophila in situ, for a better understanding of the interconnections between lipid metabolism, diets, and aging.     

The non‐existent aging program: how does it work?

Summary Aging and lifespan determination have been viewed, in the most well-accepted theories, as nonprogrammatic, and are thought to result from the evolutionary selection for early fitness at the expense of late survival. Here, recent data implicating potentially programmatic aspects of aging and lifespan determination are discussed, and analogies between programmed cell death and programmed organismal death are offered. It is hoped that the recognition of at least the possibility of a programmatic aspect, or aspects, to the determination of longevity and the process of aging will help to optimize our chances to identify appropriate therapeutic targets both for longevity enhancement and disease prevention.     

A perspective on aging in rotifers

Most research on aging in rotifers has been performed with populations, not with individuals. As a consequence, the dependent variable in these studies is usually either mean lifespan or rate of survivorship. After a brief consideration of the literature published since the last major review (King, 1969), the results of a series of experiments are presented. Males and females of three genetically distinct clones of Brachionus plicatilis were used for a factorial life table analysis at three different temperatures. The results of these experiments indicate several potential problems in using populations to study the aging process of individuals. These problems derive from the fact that lifespan is only one component of fitness, and its relative duration may not reflect the evolutionary success of the clone. That is, lifespan is free to vary in response to both stochastic and deterministic events without significantly reducing fitness. Under these conditions, neither mean lifespan nor pattern of survivorship will provide meaningful data on the determinants of individual senescence.We gratefully acknowledge the aid and advice of William R. Rice in conduct of the regression analysis. This work was supported by grants from the National Science Foundation and National Institutes of Health to CEK.     

Adaptation of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> to unfavorable growth medium affects lifespan and age-related fecundity

Experimental adaptation of Drosophila melanogaster to nutrient-deficient starch-based (S) medium resulted in lifespan shortening, increased early-life fecundity, accelerated reproductive aging, and sexually dimorphic survival curves. The direction of all these evolutionary changes coincides with the direction of phenotypic plasticity observed in non-adapted flies cultured on S medium. High adult mortality rate caused by unfavorable growth medium apparently was the main factor of selection during the evolutionary experiment. The results are partially compatible with Williams’ hypothesis, which states that increased mortality rate should result in relaxed selection against mutations that decrease fitness late in life, and thus promote the evolution of shorter lifespan and earlier reproduction. However, our results do not confirm Williams’ prediction that the sex with higher mortality rate should undergo more rapid aging: lifespan shortening by S medium is more pronounced in naive males than females, but it was female lifespan that decreased more in the course of adaptation. These data, as well as the results of testing of F₁ hybrids between adapted and control lineages, are compatible with the idea that the genetic basis of longevity is different in the two sexes, and that evolutionary response to increased mortality rate depends on the degree to which the mortality is selective. Selective mortality can result in the development of longer (rather than shorter) lifespan in the course of evolution. The results also imply that antagonistic pleiotropy of alleles, which increase early-life fecundity at the cost of accelerated aging, played an important role in the evolutionary changes of females in the experimental lineage, while accumulation of deleterious mutations with late-life effects due to drift was more important in the evolution of male traits.     

Shorter life and reduced fecundity can increase colony fitness in virtual Caenorhabditis elegans

In the nematode Caenorhabditis elegans, loss of function of many genes leads to increases in lifespan, sometimes of a very large magnitude. Could this reflect the occurrence of programmed death that, like apoptosis of cells, promotes fitness? The notion that programmed death evolves as a mechanism to remove worn out, old individuals in order to increase food availability for kin is not supported by classic evolutionary theory for most species. However, it may apply in organisms with colonies of closely related individuals such as C. elegans in which largely clonal populations subsist on spatially limited food patches. Here, we ask whether food competition between nonreproductive adults and their clonal progeny could favor programmed death by using an in silico model of C. elegans. Colony fitness was estimated as yield of dauer larva propagules from a limited food patch. Simulations showed that not only shorter lifespan but also shorter reproductive span and reduced adult feeding rate can increase colony fitness, potentially by reducing futile food consumption. Early adult death was particularly beneficial when adult food consumption rate was high. These results imply that programmed, adaptive death could promote colony fitness in C. elegans through a consumer sacrifice mechanism. Thus, C. elegans lifespan may be limited not by aging in the usual sense but rather by apoptosis‐like programmed death.     

Signal pathway of insulin and insulin-like growth factor 1 (IGF-1) as a potential regulator of lifespan

The experimental material accumulated for two decades allows concluding that regulation of lifespan has hormonal control based on the evolutionary conservative insulin/IGF-1 receptor signal pathway. Data obtained on the commonly accepted models of longevity - nematode Caenorhabditis elegans, Drosophila Drosophila melanogaster, and rodents - demonstrate that reduction of the insulin/IGF- 1 signal pathway leads to an increase of the lifespan. There is shown involvement of the longevity mechanism of a large group of genes whose products perform control of metabolism, alimentary behavior, reproduction, resistance to oxidative stress. Discussed in this review are current concepts of the insulin/IGF-1 signal system as a regulatory "longevity module" and of its possible role in prolongation of life in the higher vertebrates, including human.     

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway

Research in aging biology has identified several pathways that are molecularly conserved across species that extend lifespan when mutated. The insulin/insulin‐like signaling (IIS) pathway is one of the most widely studied of these. It has been assumed that extending lifespan also extends healthspan (the period of life with minimal functional loss). However, data supporting this assumption conflict and recent evidence suggest that life extension may, in and of itself, extend the frail period. In this study, we use Caenorhabditis elegans to further probe the link between lifespan and healthspan. Using movement decline as a measure of health, we assessed healthspan across the entire lifespan in nine IIS pathway mutants. In one series of experiments, we studied healthspan in mass cultures, and in another series, we studied individuals longitudinally. We found that long‐lived mutants display prolonged mid‐life movement and do not prolong the frailty period. Lastly, we observed that early‐adulthood movement was not predictive of late‐life movement or survival, within identical phenotypes. Overall, these observations show that extending lifespan does not prolong the period of frailty. Both genotype and a stochastic component modulate aging, and movement late in life is more variable than early‐life movement.     

Environmental effects on the expression of life span and aging: an extreme contrast between wild and captive cohorts of Telostylinus angusticollis (Diptera: Neriidae)

Most research on life span and aging has been based on captive populations of short-lived animals; however, we know very little about the expression of these traits in wild populations of such organisms. Because life span and aging are major components of fitness, the extent to which the results of many evolutionary studies in the laboratory can be generalized to natural settings depends on the degree to which the expression of life span and aging differ in natural environments versus laboratory environments and whether such environmental effects interact with phenotypic variation. We investigated life span and aging in Telostylinus angusticollis in the wild while simultaneously estimating these parameters under a range of conditions in a laboratory stock that was recently established from the same wild population. We found that males live less than one-fifth as long and age at least twice as rapidly in the wild as do their captive counterparts. In contrast, we found no evidence of aging in wild females. These striking sex-specific differences between captive and wild flies support the emerging view that environment exerts a profound influence on the expression of life span and aging. These findings have important implications for evolutionary gerontology and, more generally, for the interpretation of fitness estimates in captive populations.     

Integrating evolutionary and molecular genetics of aging

Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.     

Evolutionary ecology of aging: time to reconcile field and laboratory research

Aging is an increase in mortality risk with age due to a decline in vital functions. Research on aging has entered an exciting phase. Advances in biogerontology have demonstrated that proximate mechanisms of aging and interventions to modify lifespan are shared among species. In nature, aging patterns have proven more diverse than previously assumed. The paradigm that extrinsic mortality ultimately determines evolution of aging rates has been questioned and there appears to be a mismatch between intra‐ and inter‐specific patterns. The major challenges emerging in evolutionary ecology of aging are a lack of understanding of the complexity in functional senescence under natural conditions and unavailability of estimates of aging rates for matched populations exposed to natural and laboratory conditions. I argue that we need to reconcile laboratory and field‐based approaches to better understand (1) how aging rates (baseline mortality and the rate of increase in mortality with age) vary across populations within a species, (2) how genetic and environmental variation interact to modulate individual expression of aging rates, and (3) how much intraspecific variation in lifespan is attributable to an intrinsic (i.e., nonenvironmental) component. I suggest integration of laboratory and field assays using multiple matched populations of the same species, along with measures of functional declines.     

Signaling pathway of insulin and insulin-like growth factor 1 (IGF-1) as a potential regulator of lifespan

The experimental material accumulated for two decades allows concluding that regulation of lifespan has hormonal control based on the evolutionary conservative insulin/IGF-1 receptor signaling pathway. Data obtained on the commonly accepted models of longevity — nematode Caenorhabditis elegans, fruit fly Drosophila melanogaster, and rodents — demonstrate that reduction of the insulin/IGF-1 signaling pathway results in an increase of the lifespan. There is shown involvement in the longevity mechanism of a large group of genes whose products perform control of metabolism, feeding behavior, reproduction, and resistance to oxidative stress. Discussed in this review are current concepts of the insulin/IGF-1 signaling system as a regulatory “longevity module” and of its possible role in prolongation of life in the higher vertebrates, including human.     

The neuronal receptor tyrosine kinase Alk is a target for longevity

Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin‐like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear. We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock‐down of Alk, or expression of dominant‐negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin‐like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism‐wide insulin‐like signalling. Finally, we show that TAE‐684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.     

Mechanisms of pathogenesis and the evolution of parasite virulence

When studying how much a parasite harms its host, evolutionary biologists turn to the evolutionary theory of virulence. That theory has been successful in predicting how parasite virulence evolves in response to changes in epidemiological conditions of parasite transmission or to perturbations induced by drug treatments. The evolutionary theory of virulence is, however, nearly silent about the expected differences in virulence between different species of parasite. Why, for example, is anthrax so virulent, whereas closely related bacterial species cause little harm? The evolutionary theory might address such comparisons by analysing differences in tradeoffs between parasite fitness components: transmission as a measure of parasite fecundity, clearance as a measure of parasite lifespan and virulence as another measure that delimits parasite survival within a host. However, even crude quantitative estimates of such tradeoffs remain beyond reach in all but the most controlled of experimental conditions. Here, we argue that the great recent advances in the molecular study of pathogenesis provide a way forward. In light of those mechanistic studies, we analyse the relative sensitivity of tradeoffs between components of parasite fitness. We argue that pathogenic mechanisms that manipulate host immunity or escape from host defences have particularly high sensitivity to parasite fitness and thus dominate as causes of parasite virulence. The high sensitivity of immunomodulation and immune escape arise because those mechanisms affect parasite survival within the host, the most sensitive of fitness components. In our view, relating the sensitivity of pathogenic mechanisms to fitness components will provide a way to build a much richer and more general theory of parasite virulence.