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I.R.F. / Aging news / General / 02071803

Aging Chromatin and Food Restriction
Posted on: July 18, 2002

Aging hypotheses are resumed into two categories:

  1. first invokes extrinsic and intrinsic factors that damage intracellular or extra cellular molecular structures.
  2. second invokes changes in gene expression that are either programmed or that are bought about by normal changes in DNA structure.

Do they overlap - it is not known yet. Caloric restriction is common phenomena how to increase lifespan in living species including animals. Optimal food restriction was 50-70% in range. Such CR extends the mean and maximum lifespan.

The way it works may be: by reducing oxidative stress and damage caused by reactive oxygen species. Lin et al. describe intriguing results that may link CR to the control of gene expression and to suppression of DNA damage caused by mitotic recombination. All experiments were carried on yeasts.

Yeast undergo only a finite number of divisions, after which they die; thus, their life-span is defined by the number of divisions each cell completes. Lin et al. induced CR in yeast by limiting glucose availability or by genetically crippling their ability to sense and respond to glucose. Caloric restriction extended yeast longevity by 20 to 40%, similar to the relative life-span extension induced by CR in mammals. Of importance, this extension required the yeast genes NPT1 and SIR2. NPT1 encodes one of two enzymes that produce NAD (nicotinamide adenine dinucleotide), a key intermediate in energy metabolism. SIR2 - one of four silent mRNA regulator genes - encodes a protein that promotes a compact chromatin structure, thereby silencing gene transcription at selected loci.

As noted by Lin et al., the yeast SIR2 protein (Sir2p) is an NAD-dependent histone deacetylase, an enzyme that removes acetyl groups from the lysine residues of histone proteins (which are components of chromatin). This suggests that, through histone deacetylation, Sir2p may silence genes. In addition, the NAD requirement of Sir2p may serve to link its activity to the energy status of the cell. Thus, Sir2p may coordinate energy status with gene expression. Moreover, because by compressing chromatin, Sir2p regulates the access of many nuclear proteins to the DNA. It represses homologous recombination at the highly repetitive ribosomal DNA (rDNA) locus.

The formation and accumulation of extrachromosomal rDNA circle molecules (and possibly other DNA fragments) is a major cause of yeast aging. These circle molecules are formed by homologous recombination during the cell cycle. Homologous recombination is important for repairing damaged DNA in yeast, but can inappropriately excise DNA fragments from regions of extensive homology, such as the rDNA locus. Sir2p modulates yeast life-span largely by suppressing rDNA circle formation and loss of rRNA genes from the chromosome. Lin et al. have discovered that CR also suppresses rDNA circle molecule formation. Thus, at least in yeast, CR may extend life-span by modulating Sir2p activity and hence gene expression and recombination at silenced loci. One can now envision a model whereby the inevitable production of reactive oxygen species compromises mitochondrial efficiency, and eventually energy output, in a detrimental feedback loop. NAD levels may reflect energy status and influence chromatin silencing through the NAD requirement of Sir2p. Caloric restriction may decrease the impact of reactive oxygen species, including their indirect effect on the decline in energy production. Thus, by reducing the impact of reactive oxygen species and the resulting decrease in Sir2p activity, CR may postpone loss of chromatin silencing. But how could loss of chromatin silencing lead to aging?

The state of chromatin is essential for maintaining optimal gene expression and for suppressing homologous recombination. Loss of chromatin silencing alters gene expression, which can compromise the cell's ability to vitability, and possibly its ability to withstand stressful factors. In addition, increased recombination leads to the lethal accumulation of rDNA circles, and possibly other detrimental mutations. Life-span extension by CR delays but does not prevent aging in both yeast and mammals. Two processes - DNA replication and DNA repair - may alter chromatin silencing and recombination independently of Sir2p and NAD availability. In both processes, DNA is partly stripped, albeit transiently, of regulatory proteins, which must be rapidly reassembled. Mistakes or transient states in the reassembly process may leave chromatin susceptible to inappropriate transcription or recombination events. Because the probability of undergoing DNA replication and repair increases with the number of cell divisions, the probability of acquiring imperfectly silenced (or configured) chromatin will rise with age. Likewise, the probability that faulty DNA replication or error-prone repair will generate (or fix) mutations will rise with age. Thus, CR, or even perfect chromatin silencing, can postpone aging phenotypes, but cannot delay them indefinitely. This is consistent with the finding that CR reverses some, but not all, gene expression changes that accompany aging in rodents. How pertinent might this model be to mammals? History tells us that we can learn a great deal about human biology from model organisms. Therefore, we may expect that chromatin silencing, or chromatin maintenance in general, will play a role in the development of aging phenotypes in mammals. Indeed, silenced genes on human X chromosomes and other loci become reactivated with age, suggesting that age-related loss of silencing does occur in some mammalian cells. Moreover, preliminary studies suggest that CR will be effective in primates. Proteins such as Sir2p may well serve to link metabolism to chromatin state in mammals, including humans, although this idea has not yet been rigorously tested, even in yeast. However, owing to their complexity, mammals may engage multiple SIR2-like proteins, perhaps some that are tissue-specific. Finally, WRN, the gene responsible for Werner syndrome, a disease of premature aging in humans, is a member of a gene family that is likely to participate in recombination and other DNA repair pathways, suggesting that recombination and DNA repair may be important determinants of the rate of aging in mammals.

A fundamental difference between adult mammals and model organisms such as the yeast, the nematode, and the fruitfly is the prevalence of cancer in mammals, and essentially the lack of cancer in yeast, worms, and flies. In mammals, mutations, very likely coupled to the changes in cellular function that accompany aging, give rise to cancer, which poses an additional threat to longevity. In addition, most human cells undergo telomere attrition with successive cell divisions and aging (that is, the ends of chromosomes become progressively shorter). The extent to which telomere-induced cellular senescence contributes to human aging is not yet clear, nor is it known how telomere length contributes to the senescent phenotype of cells. In yeast, telomeres increase the compactness of nearby chromatin, but we do not yet know if this process occurs in human cells. It is intriguing, however, that telomere shortening occurs more rapidly on human X chromosomes, which could contribute to the age-dependent reactivation of X chromosome loci. The state of chromatin is now at the center of several processes known or suspected to be important in mammalian aging, suggesting, once again, that model organisms have served us well.

Source: Science 2000 September 22; 289: 2062-2063.
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