Revival: Biological Effects of Low Level Exposures to Chemical and Radiation (1992)

HYPOTHESES ON LONGEVITY HORMESIS 9

When longevity hormesis is observed, it invariably occurs without the
weight reduction observed in calorically restricted laboratory animals.21’24 25

Hypothesis VII: For homogeneous laboratory populations of eutherian
mammals housed under uniform, good laboratory conditions and kept free
of preventable disease, exposures to nonbiological, nonessential, exogenous
agents or stimuli will not slow senescent aging.

Oh, come with old Khayyam, and leave the Wise

To talk; one thing is certain, that Life flies;

One thing is certain, and the Rest is Lies;

The Flower that once has blown for ever dies.

Rubaiyat of Omar Khayyam29

In the linear Gompertz function, senescent aging is expressed through the
vulnerability parameter (G0) and a. It is hypothesized that exogenous
agents, if toxic, are without impact on these two terms per se; rather they
superimpose their injury, reversibly or nonreversibly, onto aging injury.14 If
life prolongation is achieved through exposure to exogenous agents, this
hypothesis indicates the only direct effect can be through longevity horme­
sis. Thus, pharmacological treatments, administration of antioxidants,
stress, etc., are without impact on senescence. It appears that for eutherian
mammals, housed in an optimum environment, the only way to reduce the
rate of senescence is through dietary modification and possibly physical
activity. Consistent with this view is the finding by Sacher5 that the only
factor affecting </> in eutherian mammals housed under ideal conditions is
caloric restriction. Although Sacher did report that exogenous agents could
affect the vulnerability parameter, he appears to have neglected the fact that
at zero time (usually taken at or near weaning), both treated and untreated
animals must have the same hazard function and Gompertz intercept. Thus,
Sacher applied an inappropriate extrapolation to zero time.
If Hypothesis VII is true, then, contrary to popular notion, pharmaco­
logic treatments such as antioxidants and selegiline (deprenyl) administra­
tion will not directly affect either of the two aging parameters of the linear
Gompertz function in a life-enhancing fashion. Of course, it is always
possible for pharmacologic treatments to affect dietary consumption and/
or weight gain, thereby indirectly impacting on aging. This seems likely to
have been the mechanism through which some antioxidants, in earlier
reports, enhanced longevity in mammalian population studies; by virtue of
toxicity and/or taste, these antioxidants probably acted by abating appetite,
thus reducing caloric consumption in a manner favoring longevity.16 This is
consistent with Cutler’s32 conjecture that cellular antioxidants have overlap­
ping capabilities, allowing one to replace another in a negative feedback
loop. Thus, high-level dietary vitamin E supplementation, for example,
would depress levels of other endogenous antioxidants, maintaining net
antioxidant protection at a fairly constant level.