Ribosomal protein S6 kinase 1 signaling regulates mammalian life span

Abstract

Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.

Fig. 1

Extended lifespan of mice with deletion of S6K1^-/-. (A) Kaplan-Meier survival curves for combined male and female wild-type (WT) and S6K1^-/- mice show a significant (Log-rank X²=10.52, p<0.001) lifespan extension in S6K1^-/- mice (n= 49 for WT mice and n= 48 for S6K1^-/- mice). (B) Lifespan extension was observed in female S6K1^-/- (X²=11.07, p<0.001; n= 23 for WT mice and n= 29 for S6K1^-/- mice). (C) Kaplan-Meier survival curve for male wild-type (WT) and S6K1^-/- mice shows no significant increase in lifespan in S6K1^-/- mice (Log-rank X²=0.34, p>0.05; n = 26 for WT mice and n = 19 for S6K1^-/- mice).

Fig. 2

Age-related pathology and physiological characteristics of 600 day old female S6K1^-/- mice. (A) S6K1^-/- mice had improved rotarod performance. (B and C) Increased general activity and exploratory drive was observed in S6K1^-/- mice. (D) Abundance of memory and naïve T cells in WT and S6K1^-/- mice. (E and F) Bone volume and trabecular number in WT and S6K1^-/- mice. (G and H) Insulin sensitivity and glucose tolerance of WT and S6K1^-/- mice. (I) S6K1^-/- mice were lean and (J) had reduced plasma leptin levels. (K) Body mass (p< 0.01 at all time-points), total circulating IGF-1 (L) and pituitary GH concentrations in WT and S6K1^-/- mice (M). Values are mean ± s.e.m. Asterisks indicate statistical difference compared to WT mice using two-tailed t-tests, * p<0.05, ** p<0.01 and *** p<0.001. n= 6-8 per genotype.

Fig. 3

Enhanced AMPK activation by AICAR of S6K1^-/- hepatocytes, increased AAK-2 phosphorylation in rsks-1(ok1255) mutants and effects of loss of aak-2(ok524) on longevity and physiology. (A) AICAR-stimulated AMPKα2 activity in isolated hepatocytes from S6K1^-/- mice. (B) Phosphorylation of AAK-2 Thr243 in rsks-1(ok1255) null mutants subjected, or not, to RNAi for par-4, the worm LKB kinase which effects this phosphorylation (C) Lifespan of rsks-1(ok1255) nulls with mutation of aak-2(ok524). (D to F) Body length, onset of reproductive function and brood size phenotypes in rsks-1(ok1255) mutants with or without aak-2(ok524) mutation. In (D) rsks-1(ok1255) is significantly different (p< 0.001; one-way ANOVA) from all other groups from day 2 onwards but rsks-1(ok1255);aak-2 is not significantly different from WT or aak-2. (A) to (C) show data from one representative experiment, and (D to F) show combined data from three similar independent experiments. Values (A and D to F) denote mean ± s.e.m. In (A), n = 3, and in (D), n > 8 for each strain and time point. For (E) and (F) n > 20 for each group. Asterisks indicate statistical differences using two-tailed t-tests, * p< 0.05, *** p < 0.001.