The free radical theory of aging. Is it really a theory of aging?

The free radical theory of aging, also known as the Oxidative Damagetheory of aging is over 50 years old and is perhaps the most-studied and most venerable of all the theories of aging.   But at least one line of research suggests that whatever this theory is and however important that it might be, in fact it may not be a theory of aging.   It does not appear to apply to mice living in luxury mouse resorts.

The free radical theory of aging

The free radical theory of aging holds that aging is due to the accumulation of DNA, tissue and organ damage created by free radicals.  Free radicals (ROS or Reactive Oxygen Species) are produced as a result of natural metabolism, by exposure to UV and X-rays, by exposure to certain toxic chemicals including heavy metals, and by consuming certain foods.  ROS ions steal electrons from lipids in cell membranes, a process called lipid peroxidation.  A chain of damaging events can be let loose from a single ROS molecule as unstable fatty acid radicals propagating in tissues and within cells produce other unstable radicals.  The result can be cell death, damage to DNA or mitochondrial DNA, mangled chromosomes, protein cross-linking, cell apoptosis (suicide), genetic mutations, damaged mitochondria, mutated germ cells and other forms of cell havoc. The damage can show up in many ways including skin erythema, hair loss, atherosclerosis and other forms of vascular damage, internal bleeding, cataracts, cancers, hypertension, type 2 diabetes, weakened immune systems, sterility, mutations in offspring, cancers, Alzheimer’s disease, premature aging and death.   The idea of avoiding stress and radiation, eating foods rich in antioxidants (ref)(ref) or taking antioxidant supplements (ref) is to avert such damage.

Up to a few years ago, most students of aging thought that oxidative damage was the primary cause of aging.  The evidence implicating free radicals in degenerative biological processes is overwhelming(1998 ref)(1983 ref (1991 ref) )(1999 ref) (2001 ref)(citation list ref).  The newer theories of aging continue to see oxidative damage as very important in the aging process, but part of a larger picture.  But the research described here questions whether the theory is dead, at least as a theory of aging.

Mouse experiments

Arlan Richardson is a well-known researcher who has long been studying free radicals and their biologic effects.  See, for example, his 2006 Powerpoint Presentationon The Basics of Free Radical Chemistry and Their Biology.  Richardson gave a presentation at the recent AAAS meeting describing mouse research that throws into question whether free radicals really affects aging.  The presentation called “Current Status of the Free Radical Theory of Aging” is not available in print or online but I will repeat some of the information in the slides here and cite applicable earlier publications by Richardson.

Part of the research Richardson described involved working with transgenic or knockout mice whose natural anti-oxidant defenses were disabled and checking their lifespans against those of comparable normal mice.  Only 1 of 20 Tg/KO mouse models tested showed a shortened lifespan as predicted by the free radical theory of aging, that model being SOD-/- mice.  And there is a special explanation for the shortened lifespans in that one strain.  Survival graphs were shown for mice in which CuZnSOD, Catalase, MnSOD, Gpx-4 antioxidant defenses were knocked out.  Not only did the mice have the same maximum lifespan as normal mice, but also at any age roughly the same number of mice survived.  The knockouts did, however, show signs of oxidative damage, increased cancers and sickness.  Inserting extra antioxidant defense genes also seemed to have no significant effects on the lifespans of these mice. 

These mice were all kept in clean cages with exercise wheels and were well fed.  They lived in mouse-equivalents of 4-star resorts with exercise club facilities.  In these gated resorts the mice were free of predators and free of many disease conditions to be found in the wild.

Conclusions of the study were:

 1.      Oxidative damage/stress plays a role in aging ONLY in a stressful environment (For example, suboptimal environment or short-lived genotype).”

 2.       Oxidative damage/stress plays a minimal role in aging in long-lived mice maintained in an optimal environment.”

Actually the theme described in the Richardson presentation goes back some time.  One of the key findings was telegraphed in a 2003 paper he co-authored Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging and in the 2009 publication he co-authored Mice Deficient in Both Mn Superoxide Dismutase and Glutathione Peroxidase-1 Have Increased Oxidative Damage and a Greater Incidence of Pathology but No Reduction in Longevity.  “Thus, these data do not support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice and do not support the oxidative stress theory of aging.” Nonetheless, the knockout mice got sicker. “Consistent with the important role for oxidative stress in tumorigenesis during aging, the incidence of neoplasms was significantly increased in the older Sod2+/−Gpx1−/− mice (28–30 months).”

The idea that oxidative damage may not be a cause of aging but rather is a consequence of aging was raised in an earlier blog entry Oxidative damage – cause or effect?

Do the results apply to humans? 

I speculate that the answer is “possibly” if not “probably.” Most of us in the US live pretty well-protected lives.  We do not have to worry about large predators that can eat us.  We get enough food even if we do not choose healthy food and most of us do not have to worry about shelter.  So what happens is a) the ravages of oxidative damage build up with age including all kinds of diseases and cancers, and b) yet our average lifespans continue to increase.  We get a lot of sicker older people.  If this line of reasoning is correct, strengthening our antioxidant defenses through diet, supplements and lifestyle interventions might not lead us to live longer, but may well result in us living healthier in old age.