give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging. The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander in 1967. By the early 1980s there was significant experimental support for this idea in the literature. By the early 1990s experimental support for this idea was substantial, and furthermore it had become increasingly evident that oxidative DNA damage, in particular, is a major cause of aging. In a series of articles from 1970 to 1977, PV Narasimh Acharya, Phd. (1924–1993) theorized and presented evidence that cells undergo "irreparable DNA damage", whereby DNA crosslinks occur when both normal cellular repair processes fail and cellular apoptosis does not occur. Specifically, Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate." Age-associated accumulation of DNA damage and changes in gene expression In tissues composed of non- or infrequently replicating cells, DNA damage can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damage is usually measured directly. Numerous studies of this type have indicated that oxidative damage to DNA is particularly important. The loss of expression of specific genes can be detected at both the mRNA level and protein level. Other form of age-associated changes in gene expression is increased transcriptional variability, that was found first in a selected panel of genes in heart cells and, more recently, in the whole transcriptomes of immune cells, and human pancreas cells. Another complex form of transcriptional changes in aging tissues is the breakdown of gene to gene coordination, on the basis of the transcriptional interrelations between genes. Brain The adult brain is composed in large part of terminally differentiated non-dividing neurons. Many of the conspicuous features of aging reflect a decline in neuronal function. Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to 2008 in at least 29 studies. This DNA damage includes the oxidized nucleoside 8-oxo-2'-deoxyguanosine (8-oxo-dG), single- and double-strand breaks, DNA-protein crosslinks