CSC groups demonstrate key lifespan gene

In Greek mythology, when the goddess Eos asked of Zeus that her lover Tithonus be made immortal, she forgot to ask that he also not age. So entwined are the gradual decrepitations of ageing and the eventual death to which they lead that Eos – in omitting the distinction –inadvertently condemns Tithonus to eternal decay. As she leaves him on his own to babble endlessly, Tithonius’ stagnation reminds us that death is Nature’s best mechanism for making way for new blood.

From another perspective, many lives that deserve to be well-lived are limited by the diseases of ageing; the elixir that would postpone or even abrogate those conditions eludes us as much as ever.Or does it?

Now, a study carried out by a team of researchers including CSC Cellular Stress’s Angela Woods and Dave Carling, and led by new Group Head Dominic Withers Metabolic Signalling Group; Group member Agharul Choudhury also contributed) identifies a key gene that is involved in the regulation of mammalian life span. Ribosomal protein kinase 1 (S6K1) is a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway, which co-ordinates nutrient availability with cell growth and proliferation, protein synthesis, and transcription.

Aurora (Eos) Taking Leave of Tithonus. (Public Domain)

It has been known for decades that restriction of nutrient intake without malnutrition, termed caloric restriction (CR),increases life span and reduces age-related pathology in a number of organisms, including mammals. Most recently CR has been shown to operate in primates. Previous work in lower organisms has implicated the mTOR pathway in mediating some of the effects of CR in lower organisms but the current study is the first to investigate the role ofS6K1 signalling in the regulation of mammalian ageing. The team found that mutant mice lacking S6K1 succumbed to the ravages of ageing more slowly than their S6K1-replete peers, as measured by a number of age-sensitive biomarkers, including motor and neurological function,and exploratory drive.

Physiological and gene expression analysis revealed that S6K1 null mice strongly resembled mice under conditions of CR. Crucially, the animals exhibited increased AMP-activated protein kinase (AMPK) activity in key metabolic tissues. AMPK has an important role as a master fuel gauge in the regulation of energy homeostasis and is the target for several commonly used drugs for type 2 diabetes including metformin.

Although disruption of the mTOR pathway by removal of S6K1 did not workto prolong life in males in the same way as it did in females, themutant males did have some of the health advantages seen in the femalemice.

Previous studies have revealed an apparent trade-off between sex and longevity: CR may prolong life, but it delays the onset of sexualmaturity and reduces fecundity. As part of this new study, the team found increased longevity and delayed fecundity in rsks-1 mutants of the nematode worm C. elegans, which lack the S6K1 homologue.Again, they discovered increased AMPK levels in the worms, reinforcing the importance of AMPK in longevity.

The study suggests that inhibition of S6K1 or activation of AMPK by pharmacological intervention may alleviate ageing-related disease.Indeed, the mTOR inhibitor rapamycin – a drug commonly used as an immunosuppressant in transplant medicine – has recently been shown to increase lifespan in mice, and this new study indicates that this may occur by inhibition of S6K1.

Whether or not Eos could have relied on a treatment that inhibits S6K1to prolong Tithonus’ lifespan is uncertain, but it may be that their old age would have brought fewer ailments.

Stefan Janusz

This work appeared in Science
Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J.,Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani,F., Woods, A., Robinson, I. C. A., Schuster, E., Batterham, R. L.,Kozma, S. C., Thomas, G., Carling, D., Okkenhaug, K., Thornton, J. M.,Partridge, L., Gems, D., Withers, D. J., October 2009. Ribosomal protein s6 kinase 1 signaling regulates mammalian life span. Science 326 (5949), 140-144.

(image at top right): Eos pursues a young Tithonus. (Louvre)

Eos pursues a young Tithonus. (Louvre)