L'inibizione della protein kinase A (PKA) allunga la vita:
Ageing Res Rev. 2010 Feb 23. [Epub ahead of print]
Protein kinase A signaling as an anti-aging target.
Enns LC, Ladiges W.
Department of Comparative Medicine, University of Washington, Seattle,
WA 98195.
Protein kinase A (PKA) is a multi-unit protein kinase that mediates
signal transduction of G-protein-coupled receptors through its
activation by adenyl cyclase (AC)-mediated cAMP. The vital importance
of PKA signaling to cellular function is reflected in the widespread
expression of PKA subunit genes. As one of its many functions, PKA
plays a key role in the regulation of metabolism and triglyceride
storage. The PKA pathway has become of great interest to the study of
aging, since mutations that cause a reduction in PKA signaling have
been shown to extend lifespan in yeast, and to both delay the
incidence and severity of age-related disease, and to promote leanness
and longevity, in mice. There is increasing interest in the potential
for the inhibition or redistribution of adiposity to attenuate aging,
since obesity is associated with impaired function of most organ
systems, and is a strong risk factor for shortened life span. Its
association with coronary heart disease, hypertension, type 2
diabetes, cancer, sleep apnea and osteoarthritis is leading to its
accession as a major cause of global ill health. Therefore, gene
signaling pathways such as PKA that promote adiposity are potential
inhibitory targets for aging intervention. Since numerous plant
compounds have been found that both prevent adipogenesis and inhibit
PKA signaling, a focused investigation into their effects on
biological systems and the corresponding molecular mechanisms would be
of high relevance to the discovery of novel and non toxic compounds
that promote healthy aging. Copyright © 2010. Published by Elsevier
B.V.
PLoS One. 2009 Jun 18;4(6):e5963.
Disruption of protein kinase A in mice enhances healthy aging.
Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, McKnight GS, Rabinovitch PS, Ladiges WC.
Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America.
Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIbeta, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIbeta(-/-)) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIbeta(-/-) male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging.
Inibitori, ad esempio, i soliti noti:
melatonina http://www.ncbi.nlm.nih.gov/pubmed/15230863
acido caffeico http://www.ncbi.nlm.nih.gov/pubmed/10742602 (indovinate da dove prende il nome [
])
curcumina http://www.ncbi.nlm.nih.gov/pubmed/7511111
