Accumulation of DNA damage due to failing repair with advancing age is one of the key molecular pathologies in aging. Lipid peroxidation is a main source of endogenous damage in tissue DNA and is linked to chronic inflammatory processes underlying numerous degenerative diseases. Polyunsaturated fatty acids (PUFAs) are the direct source of this damage. Various PUFAs with different oxidizability are present as basic building blocks in biological membranes and serve as precursors for local signaling molecules which modulate the strength of immune response, growth and tissue maintenance. The most unstable PUFAs of the n-3 and n-6 series cannot be manufactured by mammals and are obtained solely from dietary sources. This offers means of manipulating their content in tissues simply by food choices. Recent scientific literature suggests that longevity even within the same species correlates with lower content of the highly unsaturated n-3 PUFAs.
I suggest that altering the PUFA species particularly in the inner mitochondrial membranes which are the source of O2 radicals and located in close proximity to mtDNA would have similar effects as the mitochondrially targeted antioxidants and result in increased DNA stability and better durability of the organism. Examples of some common lipid peroxide derived DNA adducts will be presented and discussed in the context of the increased consumption of PUFA rich seed oils and the recent “epidemic” of degenerative diseases. An alternative to the popular recommendation to counteract the proinflammatory n-6 overload with the n-3 supplements will be considered consisting of lowering the n-6 and total dietary PUFA intake. I argue that substituting the nonessential part of the n-3/n-6 PUFAs in biological membranes with the alternative least unsaturated n-9 PUFA which can be manufactured by the body de novo and is found in some young tissues would improve resistance to various stressors and decrease lipid peroxidation. This should result in lower levels of endogenous DNA damage and hopefully postpone the aging process. The pro-growth activities of the n-6 derived eicosanoids will be also weighted against the available evidence that similar biologically active molecules can be manufactured from the n-9 PUFAs.