Comparative Biology and the Search for Longevity-Associated Genes

One of the primary goals of the aging research community is to determine exactly how aging progresses from moment to moment at the detailed level of genes and cellular biochemistry. This is a sizable task, not particularly driven by any application in medicine, and will be only incrementally more advanced by the time that rejuvenation therapies based on the SENS model of damage repair are a going concern. The big advantage of the damage repair approach is that it bypasses the need to understand exactly how aging progresses: since the root cause damage is known, it is possible to make progress immediately and quantify the resulting benefits along the way.

If one was to go about searching for genetic contributions to longevity, however, then the method here is a decent way to go about it. The standard problem in this space is one of complexity and limited resources: there are a lot of genes, and only so many scientists with sufficient funding to look for the needles in the haystack. The researchers here reduce the size of the problem by comparing the genomes of closely related rodent species with varying life spans; the set of genetic differences, much smaller than an entire rodent genome, should include those genes most influential on life span.

As an adaption to different environments rodents have evolved a wide range of lifespans. While most rodents are short-lived, along several phylogenetic branches long-lived species evolved. This provided us a unique opportunity to search for genes that are associated with enhanced longevity in mammals. Towards this, we computationally compared gene sequences of exceptional long-lived rodent species (like the naked mole-rat and chinchilla) and short-lived rodents (like rat and mouse) and identified those which evolved exceptionally fast. As natural selection acts in parallel on a multitude of phenotypes, only a subset of the identified genes is probably associated with enhanced longevity.

A set of 250 identified positively selected genes (PSGs) in liver tissue exhibited a highly significant pattern of down-regulation in the long-lived naked mole-rat and up-regulation in the short-lived rat, fitting the antagonistic pleiotropy theory of aging. Moreover, we found the PSGs to be enriched for genes known to be related to aging. Among these enrichments were "cellular respiration" and "metal ion homeostasis", as well as functional terms associated with processes regulated by the mTOR pathway: translation, autophagy, and inflammation. Remarkably, among PSGs are RHEB, a regulator of mTOR, and IGF1, both central components of aging-relevant pathways, as well as genes yet unknown to be aging-associated but representing convincing functional candidates, e.g. RHEBL1, AMHR2, PSMG1 and AGER.

We conclude that lifespan extension in rodents can be attributed to changes in their defense against free radicals, iron homeostasis as well as cellular respiration and translation as central parts of the growth program. This confirms aging theories assuming a tradeoff between fast growth and long lifespan. Moreover, our study offers a meaningful resource of targets, i.e. genes and specific positions therein, for functional follow-up studies on their potential roles in the determination of lifespan-regardless whether they are currently known to be aging-related or not.

Link: https://doi.org/10.1371/journal.pgen.1007272

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