Marc Tatar

Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body

In Drosophila melanogaster, ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.

Chaperoning extended life

The capacity to moderate internal and external stress is arguably the central function regulating senescence in whole-animal ageing. During ageing, molecular chaperones such as heat-shock proteins are thought to combat stress-related senescent dysfunction. In transgenic Drosophila melanogaster, with varying copy numbers of the gene hsp70 encoding heat-shock protein hsp70, we found that heat-induced expression of hsp70 increased lifespan at normal temperatures. Only a brief, low level of expression was required to obtain a long-term improvement in survival.

Reproductive cessation in female mammals

In female mammals, fertility declines abruptly at an advanced age. The human menopause is one example, but reproductive cessation has also been documented in non-human primates, rodents, whales, dogs, rabbits, elephants and domestic livestock. The human menopause has been considered an evolutionary adaptation assuming that elderly women avoid the increasing complications of continued childbirth to better nurture their current children and grandchildren. But an abrupt reproductive decline might be only a non-adaptive by-product of life-history patterns. Because so many individuals die from starvation, disease and predation, detrimental genetic traits can persist (or even be favoured) as long as their deleterious effects are delayed until an advanced age is reached, and, for a given pattern of mortality, there should be an age by which selection would be too weak to prevent the onset of reproductive senescence,,. We provide a systematic test of these alternatives using field data from two species in which grandmothers frequently engage in kin-directed behaviour. Both species show abrupt age-specific changes in reproductive performance that are characteristic of menopause. But elderly females do not suffer increased mortality costs of reproduction, nor do post-reproductive females enhance the fitness of grandchildren or older children. Instead, reproductive cessation appears to result from senescence.

Egg load as a major source of variability in insect foraging and oviposition behavior

Foraging and oviposition behavior of insects directly influences offspring production and fitness, and is therefore particularly amenable to analysis with optimization models. These models have identified two general constraints on female fitness: host availability and egg complement. Research on insect oviposition has thus far focused on external, environmentally-derived cues such as host density and quality. Here we review recent studies and suggest that insects adjust their foraging and oviposition behavior in response to their perceived risk of becoming egg limited

Insulin regulation of heart function in aging fruit flies.

Insulin-IGF receptor (InR) signaling has a conserved role in regulating lifespan, but little is known about the genetic control of declining organ function. Here, we describe progressive changes of heart function in aging fruit flies: from one to seven weeks of a flys age, the resting heart rate decreases and the rate of stress-induced heart failure increases. These age-related changes are minimized or absent in long-lived flies when systemic levels of insulin-like peptides are reduced and by mutations of the only receptor, InR, or its substrate, chico. Moreover, interfering with InR signaling exclusively in the heart, by overexpressing the phosphatase dPTEN or the forkhead transcription factor dFOXO, prevents the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on lifespan. The aging fly heart is a model for studying the genetics of age-sensitive organ-specific pathology.

Slow aging during insect reproductive diapause: why butterflies, grasshoppers and flies are like worms

Diapause is a state of arrested development accompanied by physiology for somatic persistence. Diapause is common in many invertebrates and is familiar to biogerontology in the context of Caenorhabditis elegans dauer. Among insects, diapause may occur in embryos, larvae, pupae or adults. At the adult stage, reproductive diapause arrests development of oogenesis, vitellogenesis, accessory gland activity, and mating behavior. Reproductive diapause has been well studied in monarch butterflies, several grasshoppers, and several Diptera, including Drosophila and Phormia. In monarchs and in grasshoppers, reproductive diapause physiology has been experimentally induced by the surgical removal of the corpora allata, the source of adult juvenile hormone; allatectomy in each case was found to double adult longevity. Among Drosophila, the endemic D. triauraria of Japan, and D. littoralis of Finland over-winter as adults in reproductive diapause. How D. melanogaster winter is poorly understood, but reproductive diapause can be cued by cool temperature. In laboratory studies, the mortality rates of post-diapause D. melanogaster are similar to rates of newly enclosed, young flies. This implies that senescence during diapause is slow or negligible. Slow aging during the diapause period may involve elevated somatic stress resistance as well as reallocation of resources to somatic maintenance. Reproductive diapause in Drosophila is proximally controlled by down regulation of juvenile hormone, a phenotype that is also produced by mutants of the insulin-like receptor InR, homologue of C. elegans daf-2. We propose neuroendocrine control of reproductive diapause in D. melanogaster that includes phenotypic plasticity for rates of senescence.

Drosophila germ-line modulation of insulin signaling and lifespan

Ablation of germ-line precursor cells in Caenorhabditis elegans extends lifespan by activating DAF-16, a forkhead transcription factor (FOXO) repressed by insulin/insulin-like growth factor (IGF) signaling (IIS). Signals from the gonad might thus regulate whole-organism aging by modulating IIS. To date, the details of this systemic regulation of aging by the reproductive system are not understood, and it is unknown whether such effects are evolutionarily conserved. Here we report that eliminating germ cells (GCs) in Drosophila melanogaster increases lifespan and modulates insulin signaling. Long-lived germ-line-less flies show increased production of Drosophila insulin-like peptides (dilps) and hypoglycemia but simultaneously exhibit several characteristics of IIS impedance, as indicated by up-regulation of the Drosophila FOXO (dFOXO) target genes 4E-BP and l (2)efl and the insulin/IGF-binding protein IMP-L2. These results suggest that signals from the gonad regulate lifespan and modulate insulin sensitivity in the fly and that the gonadal regulation of aging is evolutionarily conserved.

Long-term cost of reproduction with and without accelerated senescence in Callosobruchus maculatus : analysis of age-specific mortality

Age‐specific mortality is measured to characterize the costs of reproduction in the beetle Callosobruchus maculatus, providing explicit details of the timing, duration, magnitude, and acceleration of mortality. We experimentally manipulated reproductive effort in four cohorts of 200 individually housed females by controlling exposure to males and to an artificial oviposition substrate. We demonstrate that (1) early reproduction produces long‐term increases in age‐specific mortality; (2) egg‐laying effort affects the onset of age‐specific mortality but not its shape or rate of change; and (3) mating with subsequent reproduction increases the rate of change in age‐specific mortality relative to virgins. Accelerated senescence is defined demographically as an increase in the rate of change of age‐specific mortality. Our results challenge the hypothesis that reproductive effort accelerates senescence but provides evidence that mating itself may have this effect.

Aging of the innate immune response in Drosophila melanogaster

Increased activation of the innate immune system is a common feature of aging animals, including mammals and Drosophila melanogaster. With age, D. melanogaster progressively express higher levels of many antimicrobial peptides. It is unknown, however, whether this pattern reflects age‐dependent changes in the function of the immune system itself or arises simply because aged adults have greater cumulative exposure to pathogens. Here we demonstrate that aged D. melanogaster transcribe more antimicrobial diptericin when experimentally exposed to septic bacterial infections. This strong net response in older females is the result of persistent diptericin transcription upon septic exposure, whereas young females rapidly terminate this induction. In contrast to their response to septic exposure, when exposed to killed bacteria aged females have less capacity to induce diptericin. Because this functional capacity of innate immunity declines with age, we conclude that female Drosophila undergo immune senescence. Furthermore, we show that fecundity is reduced by induction of innate immunity via the immune deficiency pathway. Consequently, maximum reproduction will occur when the immune response is tightly controlled in young females, even if this increases infection risk at later ages.