A critical facet of cellular function is the response to DNA damage, genotoxic stress, and other insults. Aging in higher animals may be influenced by the balance of cell survival versus death, a decision often governed by checkpoint proteins in dividing cells. However, adult C. A good candidate is cep-1 , whose mammalian counterpart, p53, works downstream of chk1. In mammals, p53 loss increases tumorigenesis, while specific gain-of-function alleles reduce tumor incidence but accelerate aging, suggesting a trade-off between tumor surveillance and stem cell maintenance [ 94 ].
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Intriguingly then, disabling checkpoint function in C. Modulating checkpoints so that benefits are not outweighed by detriments remains a future challenge.
Mitochondrial function is central to cellular metabolism and apoptosis, while dysfunction causes numerous age-associated diseases, including diabetes, cardiomyopathy, and neurodegeneration. Surprisingly, then, a major class of C. The first described include clk-1 , which is defective in ubiquinone biosynthesis, and isp-1 , which lacks a Rieske FeS protein of complex III [ 93 , 95 , 96 ]. Genome-wide RNAi screens identified many other mitochondrial components, all of which extend life independent of daf and daf-2 [ 33 , 34 ].
These mutants display increased developmental times, slowed behavior, and smaller broods. As expected, most diminish respiration, although it is controversial whether clk-1 does or not [ 97 , 98 ]. Evidently, levels of mitochondrial gene activity must be optimized, since severe loss of function results in lethality or shortevity [ 99 ].
How might disabling mitochondria provoke extended survival? Conceivably, it produces a lower rate of living, and consequently decreased production of reactive oxygen species ROS [ 96 ]. Alternately, perturbation of electron transport may actually increase ROS, provoking a hormetic adaptive response [ 99 ].
Or it may stimulate mitochondrial turnover and thrifty metabolism. Can this example illuminate aging in higher organisms? Perhaps yes, since heterozygous knockouts of the mouse clk-1 are longer lived, suggesting that partial loss of function can confer benefits [ ]. Dietary restriction DR , the reduction of dietary intake without malnutrition, extends life span from yeast to rodents, and likely involves evolutionarily conserved mechanisms.
Even shifting adults onto agar plates without bacterial food, but with residual nutrients from peptone and agar, robustly extends life [ , ]. Whether these regimens all pinpoint the same process is still unclear, and each one has its own merits and caveats. Recently, some exciting progress has been made in identifying genes mediating DR.
When these genes are inactivated in the adult, animals are no longer long lived under reduced dietary intake. SKN-1 has an early role in pharynx and gut specification, and a later role in the response to oxidative stress in the gut [ , ]. Nonetheless, mutants deficient in sensory transduction still respond to DR. By inference, neuronal SKN-1 must regulate the organismal response to DR through a hormonal mechanism.
Accordingly, DR globally stimulates respiration, presumably to maximize organismal energy efficiency.
Genetics of aging
Consistent with this, the mammalian FOXA regulates pancreatic glucagon production [ ]. Dissecting their respective signaling pathways promises to further open up DR to a molecular analysis. Sirtuins and related molecules have been implicated as potential mediators of DR in yeast and flies, although this remains controversial [ 62 , , ]. Conflicting reports also leave this issue unresolved in worms [ , ]. Discrepancies might arise because of unknown differences in culture conditions. Evidence also suggests that TOR target of rapamycin kinase mediates DR in flies and yeast [ , ]. TOR kinase promotes growth and protein synthesis, while its reduction dampens translation and increases recycling of cellular components through autophagy.
In worms, a reduction of TOR, the downstream S6 kinase, ribosomal initiation factors, as well as ribosomal protein subunits themselves, reduce translation and extend adult life span [ , — ]. Surprisingly, however, downstream components do extend life span beyond eat-2 , suggesting that TOR outputs independent of translation could be critical for DR. Interestingly, deletion of ribosomal subunits in S. It will be critical to understand whether longevity arises from benefits due to globally reduced translation itself or from the regulation of specific factors.
With all these longevity genes, a critical question is how do worms age, and from what do they die? With age, there is a progressive decline in body movement and pharyngeal pumping [ ]. Most striking, muscle integrity deteriorates dramatically [ ], with derangement of muscle fibers and overt changes in nuclear morphology—phenotypes reminiscent of sarcopenia, a major contributor of age-related decline in people. Surprisingly, the worm nervous system appears resilient, with little obvious change in structure or reporter expression, although function has not been critically tested.
Worms are described to die of enteric bacterial infection, and antibiotics extend life [ ]. Conceivably, infection may be secondary to a decline in enteric muscle function, which is necessary to expel bacteria. Although genotype determines the mean life span of a population, individual longevity has a large stochastic component, with several-fold differences observed even with an isogenic population in a uniform environment. Nonetheless, specific markers serve as good predictors of individual life expectancy.
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For example, stochastic induction of a hspgfp reporter predicts survival, while premature appearance of lipofuscin predicts early death [ , ]. Significantly, long-lived genotypes also delay the onset of aging and age-related disease, e. Conversely, daf or hsf-1 mutants often accelerate pathology.
Conceivably, multiple age-related diseases could be mitigated at once by targeting IIS or other longevity pathways. Animal life span is unexpectedly plastic, reflecting regulatory pathways responsive to environmental signals such as nutrients and stress. The future challenge will be to determine how these different pathways map onto and interact with each other, and decipher their molecular mechanisms.
For some, basic questions such as where and when are they required, and whether they work cell autonomously or nonautonomously need to be addressed. Another major challenge will be to clarify how global processes e.
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What tradeoffs do they entail? Do they invoke signaling events or do they passively divert resources to somatic maintenance? Finally, what are the fundamental causes of aging and how can they be offset? Is it altered protein metabolism, organellar turnover, immune function, metabolic efficiency, ROS or xenobiotic detoxification, genome stability, or all of the above? Answers to these and other questions will be key to understanding broadly conserved aspects of life span determination. I thank Dan Magner for comments on the manuscript. My apologies to colleagues whose work I could not cover.
Abstract A dissection of longevity in Caenorhabditis elegans reveals that animal life span is influenced by genes, environment, and stochastic factors. Introduction Over the last 20 years, fundamental insights into the biology of aging have emerged through the study of model genetic organisms, where undoubtedly the tiny nematode C. Download: PPT. Figure 1. Sensory Input: The Senseless Liveth Critical for making preemptive decisions that prepare the animal for times ahead, sensory perception can also dramatically influence life span. Checkpoint Control A critical facet of cellular function is the response to DNA damage, genotoxic stress, and other insults.
Melis, J. Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Education Graduate Medical Education G. Graduate Program Ph.
Genetics of ageing
Master of Science in Bioethics M. Medical Program M. Einstein Senate. Those with a single copy of the mutation also had a lower incidence of diabetes, lower insulin levels after fasting, slightly lower blood pressure, and possibly more flexible blood vessels.
This protein may be the key to this genetic fountain of youth: it plays a role in the process by which cells go dormant when they can no longer replicate, called cellular senescence. Given this discovery, Vaughan and his collaborator, Toshio Miyata of Tohoku University in Japan, developed a drug for humans that includes PAI-1 inhibition in order to potentially slow the effects of aging. This drug is currently in Phase 2 clinical trials to test its efficacy in humans. Getty Images.