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CR III Conference talk summary Summary by Dean Pommerleau |
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Speaker 8: Christiaan Leeuwenburgh - Is Aging due to Oxidative Stress, Inflammation and Apoptosis? What we have Learned from Long-life CR and Life-long Wheel Running StudiesWhy do we age - lots of theories. Glycation, oxidative stress, inflammation, etc.Among others, CR has following good effects (in animals):
Will it work in humans? Supportive evidence: Okinawans + Japanese lifespan Preview of take home message - 10% CR in humans may get you most of the benefits. May not need 30-40% CR to see LE benefits Moderately CRed, voluntary wheel running not as powerful as strict CR, but does have positive effect on mean lifespan in rodents. No effect on max lifespan.
Free radical theory of agingLets look at evidence if important. Looks promising...Mitochondria are major source of free radicals (ROSs) General Free Radical Theory of aging says damage from ROSs on lipids, proteins and nuclear DNA result in aging. Mitochondrial free radical theory of aging says important damage from free radicals is in mitochondria - mitochondrial DNA gets messed up. CR reduces exposure of muscles to free radicals during aging. Free radical exposure usually goes up w/ aging. Very Moderate CR (8% restriction) is all it takes to reduce free radical production. Exercise + very moderate CR leads to greater reduction in free radicals than CR alone. Both CR and wheel running reduce free radical exposure. Together they do better than either alone. When mitochondria messed up, a lot can go wrong...
In mammals - animals that exhibit high mitochondrial DNA damage have shorter lifespan on a species by species basis. Long-lived animals (e.g. horses) have less accumulation of mitochondrial DNA damage than short-lived ones (e.g. mice and rats).
Recent refinements/findings:Mitochondrial "age" differently BETWEEN organs and may age differently WITHIN organs as well.In other words, free radical impact on aging may be more complicated than we thought. Skeletal muscle shows less mito damage in CR rats, but heart shows no difference. There are several types of mitochondria in skeletal muscles and heart - each reacts differently to CR. Further complications... Previous literature may be clouded because of these recently discovered complexities. Previous literature only looked at one type of mitochondria, or used other crude methods to measure mitochondrial damage w/o discriminating two types. Recent work in his lab paints complicated picture. Subtle stuff going on w/ two different types of mitochondria. Inside one type of mitochondria, he saw dramatic increase in very specific oxidative damage with age. But not in the other mitochondria. Bottom Line: Two types of mitochondria appear to age differently. Probably will require modifications to free radical theories of aging, but we need a lot more data/info. He's going to look at CR's effects on each mitochondria type. Looked at effects of 8% dietary restriction on diaphragm muscle. Striking result - only 8% CR increased key antioxidant enzymes. Very interesting. Inflammation Theory of Aging:Let's look at it.Muscles very important for health longevity. Very metabolically active tissue. General theory - specific chemicals associated with inflammation and inflammation response increase w/ age - TNF-alpha, NF-beta, CRP, oxidized LDL. Body's response to inflammation creates problem - heart disease etc. CR reduces this increase. Aspirin reduces them as well. CR dramatically reduces CRP level in rodents, and does it very quickly (only a couple months of CR required). Exercise + CR drops CRP even further. But Exercise + CR doesn't increase max LS. He's looking into why... TNF-alpha is a double edged sword. Can do good things, but also nasty things - depending on level and tissue. Can induce cell death (apoptosis). Inflammation marker TNF-alpha goes up w/ age, and doesn't go up in aged CR animals. Impact of aging on muscles depends on muscle fiber type. Some fiber types get damaged w/ age. Others don't. CR prevents damage to those that do. Muscle fibers don't die on CR.
Aging and Protein Aggregation - Cross linking
Apoptosis Theory of AgingCells die (kill themselves) over time, and this may contribute to aging.Apoptosis: Cell suicide that occurs when cell gets messed up enough. Such orderly death helps to prevent death of these cells from messing up its neighbors. Apoptosis important in humans - as we age, cells in our muscles undergo apoptosis and lead to dysfunction (e.g. incontinence in men). But sometimes apoptosis is a good thing - don't want to prevent it completely. Helps clean things up as we age. What triggers apoptosis? There is link between mitochondria and apoptosis. When messed up, mitochondria release chemicals that trigger apoptosis. They are the trigger for programmed cell death. But not quite so simple (again). CR blocks apoptosis - prevents programmed cell death. But perhaps CR prevents damage that would trigger apoptosis - so you don't need to kill off your cells via apoptosis. Important: In short lived tissue (liver) - apoptosis INCREASES with CR - a good thing to prevent cancer in liver. But in heart and skeletal muscles (post-mitotic), CR results in DECREASED apoptosis - preserving the cells that can't be replaced. Isn't CR a nice thing... Not just muscle fiber count improved with CR, CR also improves muscle FUNCTION. CR'ed muscles in aged animals are stronger, once animal's size is controlled for. Neurons in brain die from apoptosis more with age. CR attenuates this effect. Again we see long lived cells (brain cells) dying less frequently with CR. Some studies show rodent behavioral benefits of CR (e.g. maze running) - could be a result of cognitive benefits or physical benefits. He's investigating genetically long- and short-lived mice to see how apoptosis impacted by genetic changes. Christiaan practices CR by occasionally skipping meals - feels transient CR. Also involved in pole vaulting. Primary Interventions for people to consider:
His Intuition - start CR later. In your 30s. Doesn't suggest aerobic exercise unless to avoid obesity in middle age, and not in elderly. Perhaps walking. But need to maintain muscle mass - focus on resistance training. Too much aerobic exercise (e.g. marathon runners) can be bad. Moderation is the right thing to do. Don't overemphasize aerobics. Evolutionary - we're not designed to run long distances - short bursts to escape predators. He has hunch that only 10% CR may be sufficient to get most of CR longevity benefits. But only a hunch... Q: Michael Rae - Is apoptosis a cause of "aging", or a downstream symptom of aging? A: We don't know. Could be. |