Searching for Similarities in the Biochemistry of Long-Lived Mammals

Portions of the aging research community study various long-lived mammals, such as naked mole-rats, bowhead whales, elephants, and Brandt's bats. In most cases research projects compare a long-lived species with another species that is similar but short lived; consider the many papers examining the differences between naked mole-rats and mice or rats, for example. Naked mole rats and mice are about the same size, but the naked mole-rats live an order of magnitude longer. The hope is that such large differences in life span should help to illuminate those areas of cellular biochemistry most important in determining the pace of aging.

At this stage in the growth of the comparative biology of aging it is still a question mark as to just how much can be done with this knowledge, once obtained. Will it be practical to port over aspects of the biology of long-lived mammals to humans any time soon? Given the lengthy, expensive, and so far largely fruitless struggles to find ways to make human biochemistry undergo the beneficial calorie restriction response without actual calorie restriction, a mere change of state in one species, I have to think that we shouldn't be holding our breath waiting for medicine based on the biochemistry of other species. Controlling the operation of metabolism to this degree has been demonstrated to be a substantial challenge given present capabilities. Progress will occur, but for now there are far more effective paths forward, such as the SENS approach of repairing our existing metabolism rather than making attempts to change its operation.

In the research linked below, researchers take the approach of looking at the genetics and biochemistry of a few different long-lived mammal species, searching for similarities between them. In theory these species are long-lived for broadly similar evolutionary reasons despite their differences, or at least the hope is that evolutionary pressures converge at similar mechanisms for longevity assurance in species in the same portion of the tree of life. This may or may not be the case, of course, but it seems sensible to try an investigation along these lines if the goal is to better understand exactly how mammalian biochemistry gives rise to such large variations in life span between species.

Adaptive sequence convergence of the tumor suppressor ADAMTS9 between small-bodied mammals displaying exceptional longevity

For several decades, it has been well recognized that there is strong correlation between lifespan and body mass, with larger species typically living longer than smaller species. There are, however, several species that violate this general rule, living much longer than expected given their small size and high metabolic rates. Of particular interest are the microbats, several species of which demonstrate longer maximum lifespans than any other mammals when controlling for body size. In addition to their exceptional longevity, microbats appear to be resistant to neoplasia and remain healthy and reproductively capable throughout the majority of their lives. Much like the microbats, the naked mole-rat lives approximately three times longer than expected given its small size, is remarkably resistant to neoplasia and displays no symptoms of aging well into its second decade.

Although once thought to be rare, there have been numerous recent studies demonstrating adaptive sequence convergence between a variety of species displaying convergent traits. These studies have highlighted genes that have been repeatedly targeted during the evolution of a given trait. For example, the evolution of echolocation in bats and toothed whales appears to be driven, in part, by common mutations. This and other evidence demonstrates that common selective pressures can drive common mutations in relevant genes.

The evolution of extreme longevity in microbats and the naked mole-rat is likely attributable to a lack of extrinsic sources of mortality in these species. Bats, being nocturnal and capable of flight, generally contend with few predators. Likewise, the naked mole-rat lives in subterranean burrows where the risk of predation is low. Several theories of aging suggest that a lack of extrinsic sources of mortality will result in selection for longer lifespan. For example, according to the antagonistic pleiotropy (AP) theory of aging, a mutation can be beneficial during development, but have late-onset deleterious effects. AP is expected to be more prevalent in species with high levels of extrinsic mortality since most individuals are unlikely to survive long after reaching sexual maturity, therefore there will be little pressure to select against the deleterious effects that manifest later in life. Also, the disposability theory of aging suggests that there exists a trade-off between growth/development and repair/maintenance. In species that contend with many predators, it should be beneficial to allocate resources to grow and develop as quickly as possible rather than to invest in repair and maintenance since longevity is already unlikely.

According to both theories, for species that contend with numerous extrinsic sources of mortality, the decline in fitness due to aging is minimal, so selection is inefficient at promoting mutations that increase longevity. However, for species that exist in relatively safe niches, like microbats and the naked mole-rat, the strength of selection to delay senescence will be much stronger, as individuals that live longer will have higher lifetime reproductive fitness. We hypothesize that the pressure to delay senescence shared by microbats and naked mole-rat may have led to convergent sequence evolution in key longevity promoting genes. The identification of genes that have undergone convergent evolution in these long-lived species would provide a better understanding of the genetics of longevity and could potentially identify therapeutic targets for cancer and other age-related illnesses. Here we tested for adaptive convergent sequence evolution between microbats and the naked mole-rat in almost 5,000 genes conserved across a wide-range of mammals. We found that A disintegrin-like and metalloprotease with thrombospondin type 1 motifs 9 (ADAMTS9) displays numerous convergent substitutions between the long-lived species that were likely driven by positive selection.

ADAMTS9 is the most widely conserved member of the ADAMTS family and has recently been reported to be a novel tumor suppressor that is downregulated in several varieties of human cancer. Intriguingly, ADAMTS9 inhibits tumor growth by blocking the mTOR pathway, which has long been known to be associated with aging. In addition to its role in tumor suppression, ADAMTS9 has also been implicated in several age-related conditions including arthritis, type 2 diabetes, macular degeneration, and menopause. Furthermore, in C. elegans the loss of GON-1, the roundworm homolog of ADAMTS9, alters lifespan and promotes dauer formation. These effects are likely due to modified insulin and insulin-like ortholog secretion and altered insulin/IGF-1 signaling, which is also known to contribute to aging.

Although it may be possible that the observed convergent changes shared by microbats and the naked mole-rat may be the product of some non-adaptive force rather than selection for increased longevity, several lines of evidence suggest otherwise. First, the convergent substitutions are distributed along the length of the coding sequence, eliminating gene conversion or alternate exon usage as possible causes. Second, the convergent topology was strongly favored when only sites with evidence of positive selection occurring on the long-lived microbat branch were considered, suggesting that the convergence was indeed driven by selection. Finally, ADAMTS9 has previously been implicated in several aging processes and age-related diseases, supporting the hypothesis that modulation of ADAMTS9 function alters lifespan. Together, this evidence suggests that ADAMTS9 has been repeatedly targeted by selection for increased longevity in microbats and the naked mole-rat.

Comments

The Greenland shark lives around four hundred years. Sharks do not suffer from thymic involution.

Posted by: Tj Green at March 9th, 2017 3:39 AM
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