Saturday, 25 June 2011

A Biochemical Pathway Controlling Ageing

In Life Ascending, Nick Lane explores the conventional wisdom that explains away illness, disease or degeneration as a property of genes which is 'beyond the reach of natural selection'. But more recently it was discovered that a mutation in one gene can suspend this whole degenerative process!

This biochemical pathway is exploited as a trade off between longevity and sex; something first suggested by a British gerontologist by the name of Tom Kirkwood:
  • Kirkwood pictured exactly such a 'choice', on the grounds that energy is limited and everything has a cost.  The energetic cost of bodily maintenance must be subtracted from the energetic cost of sex, and organisms that try to do both simultaneously will fare less well than organisms that apportion their resources.
This is called the 'dispoable soma theory' and in this economic analogy, the Greece of the animal world is the Pacific Salmon.  This animal puts all its resource in to sex at the cost of bodily maintenance, after which its demise is astonishingly fast - a matter of days.  Reminds me of a holiday in the Mediterranean a few years ago...I digress....

So as with the trade off between elite fitness, health and longevity, we see another three-way trade-off between sex, maintenance and the rearing of offspring, which Lane tells us, is controlled by insulin.

There are mutations in life-extending genes that are called gerontogenes (any genetic elements that are involved in the regulation of aging and life span), which act to prolong life, but which have a default setting of 'shorter life'.  Sexual maturation is costly and so there is no point maturing in an infavourable environment, better to put life on hold until things improve.  So here is the rub - what we call ageing has more to do with sexual maturation and also has a role in obesity,
  • Mutations in the gerontogenes simulate silence.  They disable the signal of plenty, and instead rouse the genes concerned with bodily maintenance.   Even when food is abundant, the mutant geontogenes fail to respond.....they resist the sirens' beckoning of insulin.  The irony is that insulin resistance in humans doesn't confer longevity but adult-onset diabetes.  The problem is that overeating, coupled with a physiological determination to hoard scant resources  for better times, leads to weight gain, diabetes and earlier mortality.  A second irony: the penalty for prolonging life, deferring sex, remains resolutely in place.  It's expressed as infertility.  So it's no fluke that diabetes is linked to infertility.  Diabetes  and infertility are caused by the same hormonal swing.  Disabling insulin prolongs life only if we're hungry for much of the time, and at the potential cost of not having any children.
Lane goes on to discuss two gerontogenes that play a part in calorie restriction;  SIRT-1 and TOR.  Their presence is a function of nutrient and growth factor (insulin) levels.  Their roles are 'overlapping' but what caught my eye was the fact that,
  • ...blocking TOR represses immune and inflammatory activity, which could be beneficial, because many age-related diseases have a persistent inflammatory component.
Again, to anyone who has hung around the paleosphere long enough, this should all sound very familiar.  Lane goes onto explain the potential benefit of calorie restriction (although I'd wager equivalent if not more sustainable results from IF), if started early enough (by which he means prior to mitochondrial decline - it is OK to start sometime around middle-age),
  • By lowering free radical leak, bolstering mitochondrial membranes against damage, and boosting the number of mitochondria, calorie restriction effectively 'resets' the colic of life back to 'youth'.  In doing so it switches off hundreds of inflammatory genes, returning genes to their youthful chemical environment, while fortifying cells against programmed cell death.
Although Lane points out the lack of evidence of the benefits of CR in humans, it is at least plausible that there is a positive benefit of (CR and/or IF) in terms of health and longevity.  Of course experienced paleotards should be using IF already which means that the benefits aluded to above are all gravy!

Nick Lane's Live Ascending is an excellent read.  Highly recommended not least for the Chapter 10, Death - which I have drawn from above (and very heavily too, I might add).  The other nine chapters are equally fascinating.  Please read it!

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