The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 5 No.
6 • December 2002
Antioxidants Do Not Necessarily Prevent Aging Due to Free Radicals
antioxidants have been shown to have many healthful properties and may reduce
the risk of cancer and atherosclerosis, most studies with antioxidants have not
found antioxidants to determine maximum lifespan. When tissue antioxidants were
directly compared to maximum lifespan potential (MLSP) of various species, 10
out of 12 independent investigations by seven different laboratories found that
endogenous antioxidant enzymes and low-molecular weight antioxidants are
negatively correlated with maximum longevity, while two other studies found no
correlation. A review paper proposes that this evidence strongly
suggests that the rate of oxygen radical generation in tissues, rather than the
antioxidant capacity, is what limits lifespan.
review authors provide evidence that supports this hypothesis. They note that in
16 studies on lifelong experimental modifications of antioxidant levels by
dietary supplements, pharmacological methods, or transgenic techniques performed
in large numbers of animals, four found some increase in MLSP, whereas in the
other 12, MLSP did not change. They note that an increase in mean
lifespan was a much more frequent finding in these and other studies of this
type that they cited. Hence, they suggest that antioxidants can nonspecifically
prevent causes of death that result in premature death, but are not likely to be
effective in extending maximum lifespan.
rate of generation of free radicals by mitochondria has been identified by these
and many other researchers (including Dr. Denham Harman, originator of the free
radical theory of aging) as a likely major cause of aging. Indeed, caloric
restriction in rodents markedly decreases free radical generation by
mitochondria but does not have a consistent effect on antioxidant capacity.
Long-lived animals have been found to have constitutively lower levels of
antioxidants than short-lived animals because their mitochondria generate low
levels of free radicals. Hence, a better strategy for increasing
maximum lifespan than simply taking antioxidants that sop up excess free
radicals is to take supplements that are actually capable of reducing the
generation of free radicals by mitochondria.
way that cells reduce mitochondrial free radical generation is proton leak,
which is an uncoupling of the mitochondria from ATP-producing pathways, while
allowing protons that would have been involved in those pathways to instead move
across the mitochondrial inner membrane, releasing heat. Thermogenesis is not
the only purpose of proton leak, however, since even ectotherms such as reptiles
have proton leak.* It is proposed in a fascinating paper that proton
leak is a major mechanism for controlling mitochondrial free radical generation
and may be a key to longevity. The paper’s author notes that the
futile cycle of proton pumping and proton leak is responsible for 20–25% of
respiration in rat liver cells, while in perfused rat muscle it is 35–50% of
respiration. They also note that the proportion of respiration of mammalian
liver cells devoted to proton leak is remarkably constant at about 20% in a wide
range of species of diverse sizes.
leak is metabolically expensive, since so much caloric fuel is “wasted” by
mitochondria by this means, i.e., it is not used to make ATP, but is dissipated.
Hence, this mechanism must serve very important purposes, e.g., to control free
radical production, damage, and possibly aging. Mitochondrial uncoupling
proteins are part of the regulatory process of this proton pumping. It is known
that in brown adipose tissue, uncoupling protein 1 (UCP1) is involved. Whether
uncoupling protein 2 or 3 (UCP2 and UCP3), which are UCP1 homologs, are also
involved in this process is controversial; they may be mild uncouplers.
flavonoids that have been tested have been shown to uncouple mitochondrial
respiration. Quercetin, for example, was shown in one study to be
an inhibitor of the mitochondrial membrane permeability transition (MMPT), the
opening of an unselective pore elicited by calcium or prooxidants. MMPT is
inhibited by uncouplers of oxidative phosphorylation. Conjugated
linoleic acid (CLA) has been reported to increase the expression of UCP2 in the
mammary gland, brown adipose tissue, and white adipose tissue of mice, while
UCP3 levels in skeletal muscle were significantly increased. Olive
oil feeding induced the highest UCP1, UCP2, and UCP3 mRNA expression in rat
interscapular brown adipose tissue, as compared to sunflower oil, palm oil, and
beef tallow. In fact, olive-oil-fed rats had an increased total-body oxygen
consumption as compared to the other oils. This is a likely factor
in the healthful effects of the “Mediterranean diet.”
bottom line is that this new perspective does not undermine the free radical
theory of aging; in fact, it supports it. Taking the right amounts of the right
antioxidants is still a good idea, but in the long run, it appears it will be
necessary to reduce the free radicals created by mitochondria to increase
- Barja. Rate of generation of oxidative stress-related damage and animal
longevity. Free Rad Biol Med 33(9):1167-72 (2002).
Brand. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp
Gerontol 35:811-20 (2000).
- Santos et al. Effect of naturally occurring flavonoids on lipid peroxidation and
membrane permeability transition in mitochondria. Free Rad Biol Med 24(9):1455-61
- Stenlid. Flavonoids as inhibitors of the formation of adenosine triphosphate in
plant mitochondria. Phytochem 9:2251-6 (1970).
- Ealey et al. Effects of dietary conjugated linoleic acid on the expression of
uncoupling proteins in mice and rats. Lipids 37(9):853-61 (2002).
- Rodriguez et al. Olive oil feeding up-regulates uncoupling protein genes in rat
brown adipose tissue and skeletal muscle. Am J Clin Nutr 75:213-20