Four Scenarios to Link Progeria to Aging

In light of recent research demonstrating that the longevity-inducing drug rapamycin may treat the accelerated aging condition progeria, a researcher here offers up a fairly comprehensive commentary on what this might mean for work on "normal" aging. It is educational, but should be read with the caveat that the author has a strong conviction that the TOR gene is central in the aging process: "Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria. ... Scenario 1. Progerin is detectable in normal cells from normal elderly humans. In normal human fibroblasts, telomere damage during replicative senescence activates progerin production. In theory, progerin can accumulate. In this scenario, normal aging is caused by progerin or at least in some individuals accumulation of progerin is life-limiting. If so, progeria is a truly accelerated aging or at least accelerated component of aging. ... Scenario 2. Normal aging is caused by overactivation of TOR-centric pathways such as mTOR, MAPK and kinases of the DNA damage response (DDR). Progerin can activate DDR. In turn, DDR may activate the mTOR pathway. ... Therefore, by activating DDR pathways, progerin might also promote geroconversion. ... Scenario 3. mTOR inhibits autophagy and insufficient autophagy is involved in normal aging. Rapamycin also causes clearance of aggregation-prone proteins. In progeria, rapamycin activates clearance of progerin thus slowing down the progeric aging. Thus, rapamycin can affect both progeria and normal aging via activation of autophagy of different proteins and structures. ... Scenario 4. Two different mTOR activities are responsible for deceleration of normal and progeric aging. In progeria, this is autophagy. In normal aging, this is suppression of cellular hyper-functions ... Rapamycin would be effective in both conditions but by different reasons."



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