Haploinsufficiency of akt1 prolongs the lifespan of mice.
There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1 (+/-) mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases.
Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Aika
A
Nojima
Masakatsu
M
Yamashita
Yohko
Y
Yoshida
Ippei
I
Shimizu
Harumi
H
Ichimiya
Naomi
N
Kamimura
Yoshio
Y
Kobayashi
Shigeo
S
Ohta
Naoaki
N
Ishii
Tohru
T
Minamino
D000367:Age Factors; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism
C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt