CR4 - Edward Masoro:
Role of Hormesis in Life Extension by Caloric Restriction

• two groups of mice went through “common” study: ad lib vs 40% CR: showed better survival curve as per most CR studies
• CR in male F344 rats – slows progression of age-associated diseases. However, CRed rats had more tumors at death (this is likely just due to living longer and accumulating the tumors without having something else kill them). This is contrary to Walford’s studies, which showed less cancer in CRed.

Physiological characteristics are that of youthfulness – serum cholesterol did not increase as expected with age in CR vs ad lib. However, the liver lost ability to synthesize protein over time with aging – but because CRed started higher, they still only regressed to “normal” levels by old age.

Challenge to Concept of CR based on CALORIE restriction:

• reduction of methionine by 40% produces results as much as 40% CR
• CR should be changed to Food Restriction, as calories are not important (?)
• No – this is not correct, as another study showed that NOT reducing methionine while reducing calories still had LE effect
(Casein has lack of methionine particularly compared to other food sources)

CR is a low intensity stressor – this is why it works

There are various hypotheses on why CR works, from body fat to oxidative damage to hormesis – the subject of this speech.

What is hormesis? Phenomenon in which the response to an agent is different when the agent is high vs low intensity. For example, low amounts of a carcinogen will not cause cancer and could even prevent it (“inoculation”?), but high amounts are damaging.

Rattan’s def: hormesis is beneficial effects from cellular responses to mild, repeated stress. Hormesis as an aging retardant comes from principle that repeated low stress stimulates maintenance and repair processes.

IS CR A REPEATED LONG-TERM STRESSOR?

• seems like yes: corticosterone free and peak levels are elevated in CRed rats
• but is it a stressor with protective results? Also yes:
• post-surgical weight loss is much lower in CRed rats
• inflammatory response is much lower in CRed rats than non-CR
• heat stress survival went from 16% in ad lib to 75% in CR
• protection from toxic actions of chemicals

CR when moderate is a long term stressor, extreme CR obviously is lethal so this is an extreme stressor

Kirkwood’s theory of Disposable Soma – this could be related to hormesis because it changes the ratio of repair/damage to maintenance to be favorable

Other low-intensity stressors tested: heat, hypergravity, osmotic stress.

So what is the hormesis pathway?

• proposed by Sinclair Group: increase of pnc level, which lowered nicotinamide level, which raised sir2p activity…which had an effect on and “efferent limb” – this is still unknown and needs to be explored….which then resulted in life extension.
• It could be the enhancement of the repair processes, such as transcribed DNA error repair or rate of whole-body protein turnover.
• Work of Pashko & Schwartz – ability of CR to protect against tumors may be tied to level of adrenal function (? Missed this point)

Criticisms of hormesis;

• Neafsey’s: mortality response was discouraging, but other effects were good so this might not be a strong criticism
• Sapolsky’s: elevated levels of glucocoricoids are damaging and therefore the raised levels caused by low-level stressors would be bad? (Not necessarily, as the low levels could be instead a protectant)
• CR does not increase resistance to all stressors, especially intense stressors (wound healing, for example). Norm Wolf study of re-feeding for 4 weeks to restore healing in CRed organisms.
• Biologists have discounted the biological importance of hormesis, especially relating to life-extending action of CR
• McEwen’s allostatic load concept

Hormesis provides a unifying framework that embraces several of the other proposed hypothesis regarding the life-extending and anti-aging actions of CR. (The other likely process is a decreased rate of generation of damaging agents)

MR says: hormesis has been tried many ways but does not have conclusive results