And Now a Female-Only Longevity Mutation in Mice

Back in June, I pointed out a longevity mutation that only extends healthy life span in male mice. By way of a bookend to that discovery, here is a mutation that extends healthy life span by 20% or so in female mice only.

Researchers have identified a genetic tweak that can slow aging in mice:

Caloric restriction has long been known to extend lifespan and reduce the incidence of age-related diseases in a wide variety of organisms, from yeast and roundworms to rodents and primates. Exactly how a nutritionally complete but radically restricted diet achieves these benefits has remained unclear. But recently several studies have offered evidence that a particular signaling pathway, involving a protein called target of rapamycin (TOR), may play a pivotal role. This pathway acts as a sort of food sensor, helping to regulate the body's metabolic response to nutrient availability.

Withers and colleagues noticed that young mice with a disabled version of the protein S6 kinase 1 (S6K1), which is directly activated by TOR, bore strong resemblance to calorie-restricted mice: they were leaner and had greater insulin sensitivity than normal mice.

UC Development Aids Longevity Research

Armed with this knowledge and an appropriate mouse model for further testing, Withers and his team hypothesised that S6K1 could play a role in mammalian longevity. He began studying this hypotheses using UC’s S6K1 "knock-out" mouse models - those without S6K1.

The team determined that female S6K1 knock-out models were hyperactive and actually consumed more calories, but those calories were quickly used or "burned up," which naturally lowered levels of ATP (energy) within the cell. Decreased ATP levels in S6K1 knock-out mice increased levels of the protein kinase AMPK, resulting in a restriction of anabolic processes and an increase in longevity.

You might recall that manipulation of AMPK has also been shown to produce some of the same benefits as calorie restriction - many of the genes and proteins in these pathways have been worked on by research groups over the past five years or so. Back in 2004, manipulation of S6K1 itself was shown to produce changes that might be expected to enhance long-term health, centering around insulin signaling:

Here, we report that S6K1-deficient mice are protected against [some of the biochemical consequences of obesity]. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance.

The more recent results in S6K1 knockout mice are one small part of the flurry of research into the biochemistry of calorie restriction. Scientists are racing to explore pathways and mechanisms gene by gene and protein by protein, seeking the best place to intervene using designed drugs. The goal is to capture all the benefits of calorie restriction, or even do better, whilst minimizing or eliminating unwanted side-effects. Give it another ten years and the new scientific industry of metabolic manipulation will rival that of stem cell research, I'd wager. It certainly seems set for that sort of growth, starting from calorie restriction biochemistry and working its way outward.


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