Prestwich EG, Roy MD, Rego J, Kelley SO.
Oxidative DNA strand scission induced by peptides.
Chem Biol. 2005 Jun;12(6):695-701.
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I have a scientific question: How can aging be a risk factor for Alzheimer's? Diseases have causes, don't they?
1. Most aging humans don't get AD, and no wild animals, eating natural foods, get it, whatever their age. That includes chimps. The aging process does not cause this disease. Villagers in India who use unrefined mustard oil in their cooking do not get AD, but they age like anyone else. Sporadic AD is seen only where refined food oils are available.
2. If sporadic (non-genetic) AD takes 30-40 years to develop, then the disease must start somewhere between 30 and 40, possibly even earlier, i.e., it does not begin in old age; it begins in relatively young people, so aging may be a risk factor for the eventual outcome, but is not a factor in the origin and aetiology of the disease; AD may be time-related (slow to develop), but is clearly not age-related, in the sense that the aging process causes it.
3. Hugh Hendrie has shown that African-Americans in Indiana have 3-4 times the risk of getting AD, compared to genetically similar West Africans, so how do the latter manage to get older with much less risk of getting AD, unless they are lucky enough to avoid some dietary or toxic factor that is more common in the USA?
4. Twin discordance is common in sporadic AD; twins age at the same rate, so how come only one of them is getting AD? The most startling example of this, which triggered my investigations into diet and AD in 1990, was a discordant pair of Scottish twins, one showing plaques and tangles at autopsy, the other being completely clear of AD pathology at autopsy. Both were aging, yet only one got AD. I concluded that diet entered the picture, eventually pinning down refined, vitamin E-deficient food oils as a likely cause.
There is even suggestive evidence that sporadic AD incidence declines after the age of 90, as does the risk of breast cancer and osteoarthritis; the reason might be that most folks who were going to get these diseases have already developed them before 90, while those who are not exposed to the actual causes live on free of risk. How often do we hear of diabetes and atherosclerosis being age-related, yet there are heaps of 10-20-year-olds with type 2 diabetics in the USA, and plenty of 3-year-olds with yellow-streaked arteries!
Finally, so-called age-related macular degeneration (AMD) turns out to be mostly due to chronic dietetic deficiency of the macular pigments lutein and zeaxanthin, which are now known to improve vision, despite the person's age.
DNA Fragmentation Mechanism Involving Oxidative Stress: Relevance to Alzheimer Disease
While DNA strand breaks are stereotypical of an apoptotic program, their presence in Alzheimer disease (AD) is of such a widespread nature and numerically high scale (Su et al., 1994) that we previously argued that DNA breakage in AD did not define apoptosis and that apoptosis was unlikely to play a major role in the disease (Perry et al., 1998a,b). Supporting this, the cardinal feature of apoptosis, i.e., activation of executioner caspases, is absent in the disease (Raina et al., 2001). Therefore, rather than an apoptotic mechanism, DNA fragmentation in AD is more likely a consequence of oxidative stress (Su et al., 1997). Recently, an intriguing mechanism by which oxidative stress promotes DNA fragmentation was reported in Chemistry and Biology (Prestwich et al., 2005). Specifically, these new studies show that reactive oxygen species convert protein residues into peroxides that cleave DNA via hydrogen abstraction. Since direct oxidation of proteins is known to be an invariant feature of AD (Smith, 1996) and is, like DNA fragmentation, widespread and chronic (Smith et al., 2002), these studies likely have great relevance to the pathogenesis of AD. Moreover, these studies should serve to further emphasize the promiscuous nature of oxidative stress that, in AD, involves damage to all of the major macromolecules of the cell (Casadesus et al., 2004) and is one of the earliest cytopathological changes in disease (Nunomura et al., 2001).