Molecular mechanisms of ageing: from fat to
brain.
Mounting evidence indicates that the molecular
circuitries underlying the ageing process at a cellular, tissue and organismal
level are profoundly intertwined with the biochemical pathways whereby cell perceive the presence
of nutrients and adapt to the availability of energy substrates. In keeping
with this paradigm, ageing and age-related pathologies, while effectively
prevented by calorie restriction, are
accelerated in diabetes and obesity as conditions marked by excess availability
of nutrients and deranged cell responses
metabolic burden .
In the first part of my talk I’ll introduce this general theme focusing on
the mTOR (mammalian Target of raspamycin) cascade as an emerging link between
metabolism, longevity and age-related diseases. In particular I’ll describe the role of mTOR in cell
hyperglycemic damage and discuss its potential relevance to (stem) cell
senescence.
In the second part, I’ll address the issue of
how mTOR signaling to ageing relates with the conventional view of senescence as mediated by reactive oxygen
species and molecular/cellular oxidative damage. Central to this part will be
data generated in my laboratory on the
interplay between mTOR dependent nutrient signaling and the lifespan
determinant p66shc, a molecule recognized as a major player in ROS dependent
mitochondrial damage and related disorders. I’ll present evidence that p66shc
modulates mTOR activity in response to nutrients and insulin and promotes
mTOR-dependent obesity and insulin desensitization in mice. Interestingly,
these effects appear to be independent of pro-oxidant activities of p66 but
rather related to p66shc action as a molecular adapter linking the insulin
transducer IRS-1 with the mTOR effector S6K.
Finally, I’ll switch to brain as a target for
metabolic regulation of ageing; I’ll introduce the connection between
neurotrophic and metabolic signaling in the brain and describe how the
transcription factor CREB mediates neuroprotective gene expression and enhanced
plasticity in the hippocampus of
calorie-restricted mice. I’ll also present unpublished data demonstrating
impaired CREB activity in the cognitive brain areas of obese mice, and a
possible role of CREB in the establishment of hippocampal insulin resistance in
these animals.
The tentative length
of the talk is 45 minutes, plus discussion.
Reading:
1: Ranieri SC, Fusco S, Pani G.
p66(ShcA): linking mammalian longevity with obesity-induced insulin resistance.
Vitam Horm. 2013;91:219-41.
2: Pani G. Cell death by sugar: bittersweet TOR. Cell Cycle. 2011 Jan 1;10(1):13-4.
Epub 2011 Jan 1. Review. PubMed PMID: 21200136.
3: Ranieri SC, Fusco S, Panieri E, Labate V, Mele M, Tesori V, Ferrara
AM, Maulucci G, De Spirito M, Martorana GE, Galeotti T, Pani G. Mammalian
life-span determinant p66shcA mediates obesity-induced insulin resistance. Proc
Natl Acad Sci U S A. 2010 Jul 27;107(30):13420-5.
4: Panieri E, Toietta G, Mele M, Labate V, Ranieri SC, Fusco S, Tesori
V,Antonini A, Maulucci G, De Spirito M, Galeotti T, Pani G. Nutrient withdrawal
rescues growth factor-deprived cells from mTOR-dependent damage. Aging (Albany NY).
2010 Aug;2(8):487-503.
5: Fusco S, Ripoli C, Podda MV, Ranieri SC, Leone L, Toietta G, McBurney
MW, Sch？tz G, Riccio A, Grassi C, Galeotti T, Pani G. A role for neuronal cAMP responsive-element
binding (CREB)-1 in brain responses to calorie restriction. Proc Natl Acad Sci
U S A. 2012 Jan 10;109(2):621-6.
6: Fusco S, Pani G. Brain response to calorie restriction. Cell Mol Life
Sci. 2013 Sep;70(17):3157-70.