Protein Acetyltransferases Influence Longevity in Short-Lived Laboratory Species

Over the past twenty years a great deal of work has gone into the investigation of protein deacetylases, such as SIRT1, in the context of aging and longevity. Here, researchers note some of the evidence for the other side of the coin, protein acetyltransferases, to also influence life span in short-lived laboratory species. It seems plausible that interventions based on these mechanisms will also produce negligible effects once attempted in humans: all of these metabolic manipulations appear to scale down in their benefits as species life span increases. Treatments that make nematode worms live twice as long typically have little to no useful outcome in humans. This isn't a part of the field that is likely to produce meaningful treatments for aging, judging by the work taken place to date.

The level of acetylation on a given protein is the result of a balance in the activity of opposing families of enzymes, protein lysine acetyltransferases that attach the acetyl moieties and protein deacetylases that remove the acetyl groups. The idea that protein acetylation plays an important role in the regulation of aging began with the pioneering work on the sirtuin family of NAD+-dependent protein deacetylases. Studies in model organisms such as, flies, worms and mice, showed that genetic or pharmacological modulation of sirtuin activity influenced lifespan. While a role for protein deacetylases in aging is firmly established, the enzymes on the other side of the equation, the protein lysine acetyltransferases, have not received a proportionate share of research into understanding their potential roles in the regulation of aging.

Protein N-ε-lysine acetyltransferases (KATs) are a diverse family of enzymes. While many of these enzymes were originally identified as histone acetyltransferases, it is now clear that most, if not all, have multiple substrates. From a broad perspective, it is not surprising that KATs are likely to play key roles in the aging process. KATs modify proteins involved in many cellular processes including those linked to the hallmarks of aging.

Recent studies have now shown that several KATs are directly linked to the aging process and that genetic and pharmacological manipulation of KATs can influence lifespan. Our understanding of the link between KATs and aging clearly has a long way to go to match our understanding of sirtuins. Important questions that need to be addressed include determining the relevant aging-related cellular processes that each KAT functions in and identifying aging-relevant substrates for each KAT. It will take intensive investigation to decipher the molecular mechanisms underlying the influence of KATs on aging and lifespan.



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