Mammalian aging can be delayed with genetic, dietary and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand Geroscience research directed at extending human healthspan.

We have discovered that three longevity mutants of the nematode Caenorhabditis elegans also exhibit increased intrinsic thermotolerance (Itt) as young adults.Mutation of the age-i gene causes not only 65% longer life expectancy but also Itt. The Itt phenotype cosegregates with age-i. Long-lived spe-26 and daf-2 mutants also exhibit Itt. We investigated the relationship between increased thermotolerance and increased life-span by developing conditions for environmental induction of thermotolerance. Such pretreatments at sublethal temperatures induce significant increases in thermotolerance and small but statistically highly significant increases in life expectancy, consistent with a causal connection between these two traits. Thus, when an animal's resistance to stress is increased, by either genetic or environmental manipulation, we also observe an increase in life expectancy. These results suggest that ability to respond to stress limits the life expectancy of C. elegans and might do so in other metazoa as well.A mechanistic understanding of the physiology of aging and its relationship to organismic life-span is the subject of considerable speculation. Mutations in any one of several genes in Caenorhabditis elegans result in significant extensions of mean and maximum life-span (1-5). The age-l(hxS46) mutation leads to a 65% increase in mean life-span and a 110% increase in maximum life-span with no detectable effect on development (6) and a marginal effect on fertility (2). Mutations that affect the organism's ability to form dauer larvae (dauers) also extend life-span. The dauer is an alternate developmental stage seen under conditions of poor nutrition or overcrowding (7); dauer-constitutive mutations, such as loss-of-function (lf) temperature-sensitive (ts) mutations in the daf-2 gene, result in dauer formation at the restrictive temperature under conditions that would not normally cause dauer formation, while dauer-defective If mutations in other genes cause failure to form normal dauers under any conditions (8). Analysis of these mutations has led to proposals for partially redundant, signal transduction pathways that control entry to and exit from the dauer state (9-12). Kenyon et al. (5) demonstrated that daf-2 mutants had twice the life expectancy of wild type when grown under conditions that allow the formation of normal adults. Life-span extension was suppressed by an lf mutation in the daf-16 gene. They postulated that mutation of daf-2 activates a life-span extension mechanism dependent on daf-16. This observation has been extended by Larsen et al. (13), who showed that the daf-23(m333) mutation also confers life-span extension, that the daf-12(m20) mutant acts synergistically with daf-2(el370) to extend life-span 4-fold, and that the daf-16(m26) mutation is probably epistatic to daf-2(el370) and daf-12(m20) mutations. Van Voorhies (4) demonstrated that two mutant alleles of spe-26(it118 and hc138) were long-lived (Age) and postulated that spermatogenesis reduces C. elegans life-span.In addi...

For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.

SummaryProtein synthesis is a regulated cellular process that links nutrients in the environment to organismal growth and development. Here we examine the role of genes that regulate mRNA translation in determining growth, reproduction, stress resistance and lifespan. Translational control of protein synthesis by regulators such as the cap-binding complex and S6 kinase play an important role during growth. We observe that inhibition of various genes in the translation initiation complex including ifg-1 , the worm homologue of eIF4G, which is a scaffold protein in the cap-binding complex; and rsks-1 , the worm homologue of S6 kinase, results in lifespan extension in Caenorhabditis elegans . Inhibition of ifg-1 or rsks-1 also slows development, reduces fecundity and increases resistance to starvation. A reduction in ifg-1 expression in dauers was also observed, suggesting an inhibition of protein translation during the dauer state. Thus, mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans .

We tested the theory that reactive oxygen species cause aging. We augmented the natural antioxidant systems of Caenorhabditis elegans with small synthetic superoxide dismutase/catalase mimetics. Treatment of wild-type worms increased their mean life-span by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their life-span (a 67 percent increase). It appears that oxidative stress is a major determinant of life-span and that it can be counteracted by pharmacological intervention.

SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

Senescence is a cellular program that irreversibly arrests the proliferation of damaged cells and induces the secretion of the inflammatory mediators IL- 6 and IL-8 which are part of a larger senescence associated secretory phenotype (SASP). We screened quiescent and senescent human fibroblasts for differentially expressed microRNAS (miRNAs) and found that miRNAs 146a and 146b (miR-146a/b) were significantly elevated during senescence. We suggest that delayed miR-146a/b induction might be a compensatory response to restrain inflammation. Indeed, ectopic expression of miR-146a/b in primary human fibroblasts suppressed IL-6 and IL-8 secretion and downregulated IRAK1, a crucial component of the IL-1 receptor signal transduction pathway. Cells undergoing senescence without induction of a robust SASP did not express miR-146a/b. Further, IL-1α neutralizing antibodies abolished both miR-146a/b expression and IL-6 secretion. Our findings expand the biological contexts in which miRNA-146a/b modulates inflammatory responses. They suggest that IL-1 receptor signaling initiates both miR-146a/b upregulation and cytokine secretion, and that miR-146a/b is expressed in response to rising inflammatory cytokine levels as part of a negative feedback loop that restrains excessive SASP activity.

Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity1. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids2. A group of small molecules, traditionally used in histopathology to stain amyloid in tissues, bind protein fibrils and slow aggregation in vitro and in cell culture3,4. We proposed that treating animals with such compounds would promote protein homeostasis in vivo and increase longevity. Here we show that exposure of adult Caenorhabditis elegans to the amyloid-binding dye Thioflavin T (ThT) resulted in a profoundly extended lifespan and slowed ageing. ThT also suppressed pathological features of mutant metastable proteins and human β-amyloid-associated toxicity. These beneficial effects of ThT depend on the protein homeostasis network regulator heat shock factor 1 (HSF-1), the stress resistance and longevity transcription factor SKN-1, molecular chaperones, autophagy and proteosomal functions. Our results demonstrate that pharmacological maintenance of the protein homeostatic network has a profound impact on ageing rates, prompting the development of novel therapeutic interventions against ageing and age-related diseases.