Not All Longevity Manipulations Play Nice Together

One of the pleasant aspects of the repair approach to intervention in aging, such as that proposed in the Strategies for Engineered Negligible Senescence (SENS), is that all distinct forms of repair therapy can reasonably be expected to complement one another. Undergo a procedure to fix mitochondrial damage or break down an AGE such as glucospane, for example, and you are better off. Undergo both therapies and you will gain a commensurately greater benefit.

Unfortunately, this expectation of complementary therapies is very much not the case when it comes to attempts to slow down aging by genetic, epigenetic, or other metabolic manipulation. Metabolism is enormously complex, and even the well-studied phenomenon of calorie restriction isn't yet fully understood in terms of how the machinery of genes, proteins, and controlling signals all ties together to increase life span and improve health. Varied methods of extending life by slowing aging often turn out to operate on different portions of the same mechanism, or harmful when used together even though they are beneficial on their own.

One thing often tried by research groups that discover a novel way of slowing aging in laboratory animals is to try out the new method in calorie restricted animals: will the effects on life span complement one another and thus lead to a greater extension of life than is the case for either method on its own? Few presently known genetic alterations or other methods of slowing aging produce more than a 30% life extension in mice, and the standing record is 60-70% for growth hormone deficient mice - so at this point in time, it seems unlikely that any new life span record will be set through slowing aging without employing some complementary combination of techniques.

That this hasn't yet happened suggests that we shouldn't hold out much hope for the next five to seven years - there has, after all, been a lot of experimentation in mice over the past decade, and especially since the record set using growth hormone deficient mice. Unfortunately purely negative results don't tend to be published as often as positive results, so it's not a straightforward matter to find out which combinations of the various known methods to slow aging in mice have been tried only to fail.

Nonetheless, one example showed up recently in work on extending mouse longevity with AC5 knockout (AC5 KO) and calorie restriction, and here is a commentary on that research that clearly makes the point:

Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses

Third Incorrect Hypothesis: The most widely studied model of longevity is calorie restriction (CR). Our hypothesis was that combining these two models would produce a super longevity model. Accordingly, we placed AC5 KO mice on CR. Within a month we found that all the AC5 KO mice on CR had died. Accordingly, we had to change our hypothesis to include that the AC5 KO and CR models share similar protective and metabolic mechanisms, which could mediate longevity and health, but when superimposed are actually lethal.

This might be taken as a cautionary note on metabolic manipulation as a path to slowing aging: there are pitfalls, it is enormously complicated, and there isn't much of a roadmap in comparison to the path to repair-based strategies of the sort outlined in the SENS vision.


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