Ageing Research Reviews - Protein kinase A signaling as an anti-aging target
Linda C. Enns, Warren Ladiges#8727; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
Plant secondary metabolites (flavonoids, anthocyanins and
polyphenols) have been the subject of increasing interest as
potential agents for both disease prevention and therapy. Many
plant-derived compounds, such as those found in pomegranate,
grapeseed, apples and green tea, have been shown to have cancerpreventing
properties and to protect against heart disease and
artherosclerosis (Nakachi et al., 2000; Clifton, 2004). In addition,
some have been found to target adipocyte function, resulting
in suppression of adipogenesis in cell culture (Hsu and Yen,
2007). Extracts from green tea, crowberry, clove, cinnamon and
pomegranate have been shown to be inhibitors of PKA activity
(Moskaug et al., 2008). However, their specific mechanism of inhibition
is not known so they could be inducing harmful effects by
altering vital PKA signaling. A screening assay is therefore needed
to distinguish those compounds that specifically inhibit PKA Cand
not other PKA subunit genes.
The PKA pathway has become of great interest to the study of
aging, since mutations in this pathway that cause a reduction in
PKA activity have been shown to extend lifespan in yeast, and to
promote leanness and longevity, and resistance to stress-induced
cardiomyopathy in mice. There is increasing interest in the reduction
and/or redistribution of adiposity in conjunction with delayed
aging. Obesity is associated with impaired function of most organ
systems, and is a strong risk factor for shortened life span (Fontaine
et al., 2003). Its association with coronary heart disease, hypertension,
type 2 diabetes, cancer, sleep apnea and osteoarthritis
is leading to its accession as a leading cause of global ill health,
ahead of under nutrition and infectious disease (Kopelman, 2000).
Therefore, genes that promote adiposity through cellular signaling
pathways are potential inhibitory targets for aging intervention.
Since numerous plant compounds have been found that both
prevent adipogenesis and inhibit PKA activity, a focused investigation
into identifying and characterizing their biological effects and
molecular mechanisms would be of high relevance to the development
of novel and non-toxic compounds as a way to maintain good
health with increasing age.