Rejuvenation is the procedure of reversing the aging process, thus regaining youth. As people get older, their health worsens, strength and intelligence are thought to diminish, beauty is thought by many to go away. Historically, people in all societies have looked for a way to regain the qualities of youth. In the future however, rejuvenation may become reality through stem cells, biochemical repair and/or nanotechnology.
Numerous studies have shown that DNA damage accumulates in brain, muscle, liver, kidney, and in long-lived stem cell. These accumulated DNA damages are the likely cause of the decline in gene expression and loss of functional capacity observed with increasing age. On the other hand, accumulation of mutations, as distinct from DNA damages, is not a plausible candidate as the primary cause of aging. A calorie-restricted diet in mammals improves lifespan, and this improvement is associated with a decrease in oxidative DNA damage. Several inherited genetic defects in ability to repair DNA damage give rise to premature aging suggesting a causal relationship between DNA damage and aging. In comparisons of different mammalian species that differ in lifespan, DNA repair capacity is found to correlate with lifespan. The principal source of the DNA damages leading to normal aging appears to be reactive oxygen species, produced as byproducts of normal cellular metabolism.
If DNA damage is the underlying cause of aging, it would be expected that humans with inherited defects in the ability to repair DNA damages should age at a faster pace than persons without such a defect. Numerous examples of rare inherited conditions with DNA repair defects are known. Several of these show multiple striking features of premature aging, and others have fewer such features. Perhaps the most striking premature aging conditions are Werner syndrome (mean lifespan 47 years), Huchinson-Gilford Progeria (mean lifespan 13 years), and Cockayne syndrome (mean lifespan 13 years). Werner syndrome is due to an inherited defect in an enzyme (a helicase and exonuclease) that acts in base excision repair of DNA (e.g. Harrigan et al., 2006). Hutchinson-Guilford Progeria is due to a defect in Lamin A protein which forms a scaffolding within the cell nucleus to organize chromatin and is needed for repair of double-strand breaks in DNA (Liu et al., 2007). Cockayne Syndrome is due to a defect in a protein necessary for the repair process, transcription coupled nucleotide excision repair, which can remove damages, particularly oxidative DNA damages, that block transcription (D’Errico et al., 2007). In addition to these three conditions, several other human syndromes, that also have defective DNA repair, show several features of premature aging. These include ataxia telangiectasia, Nijmegan breakage syndrome, some subgroups of xeroderma pigmentosum, trichothiodystrophy, Fanconi anemia, Bloom syndrome and Rothmund-Thomson syndrome.
In addition to human inherited syndromes, experimental mouse models with genetic defects in DNA repair show features of premature aging and reduced lifespan (e.g. Vogel et al., 1999; Niedernhoffer et al., 2006; Mostoslavsky et al, 2006).
In rodents, caloric restriction slows aging and extends lifespan. At least 4 studies have shown that caloric restriction reduces 8-OHdG damages in various organs of rodents. One of these studies (Hamilton et al., 2001) showed that caloric restriction reduced accumulation of 8-OHdG with age in rat brain, heart and skeletal muscle, and in mouse brain, heart, kidney and liver. More recently, Wolf et al. (2005) showed that dietary restriction reduced accumulation of 8-OHdG with age in rat brain, heart, skeletal muscle, and liver. Thus reduction of oxidative DNA damage is associated with a slower rate of aging and increased lifespan.
A popular idea, that has failed to gain significant experimental support, is the idea that mutation, as distinct from DNA damage, is the primary cause of aging. As discussed above, mutations tend to arise in frequently replicating cells as a result of errors of DNA synthesis when template DNA is damaged, and can give rise to cancer. However, in the mouse there is no increase in mutation in the brain with aging (Dolle et al., 1997; Stuart et al., 2000; Hille et al., 2005). Mice defective in a gene (Pms2) that ordinarily corrects base mispairs in DNA have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly (Narayanan et al., 1997). On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation (Dolle et al., 2006).
One variation of the idea that mutation is the basis of aging, that has received much attention, is that mutations specifically in mitochondrial DNA are the cause of aging. Several studies have shown that mutations accumulate in mitochondrial DNA in infrequently replicating cells with age. DNA polymerase gamma is the enzyme that replicates mitochondrial DNA. A mouse mutant with a defect in this DNA polymerase is only able to replicate its mitochondrial DNA inaccurately, so that the mutation rate is 500-fold higher than in normal mice. Yet these mice showed no obvious features of rapidly accelerated aging (Vermulst et al., 2007). The probable explanation for the apparent lack of effect of the additional mutations in mitochondrial DNA is that, within a typical cell, there are large numbers of mitochondria and each mitochondrion can have multiple copies of mitochondrial DNA. Since most mutations are recessive, any particular deleterious mutation would not be expected to have a pronounced effect when many copies of the correct DNA sequence are present in the same and in other mitochondria in the cell. Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.
In tissues composed of non- or infrequently replicating cells, DNA damages can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damages are 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.
To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and thus they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of decrements in function, characteristic of aging, associated with accumulation of DNA damages, are given later in this article.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can 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 (1967). By the early 1980s there was significant experimental support for this idea in the literature (Gensler & Bernstein, 1981. 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 (Bernstein & Bernstein, 1991; Ames & Gold, 1991; Holmes et al., 1992; Rao & Loeb, 1992; Ames et al., 1993).
To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and thus they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of decrements in function, characteristic of aging, associated with accumulation of DNA damages, are given later in this article.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can 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 (1967). By the early 1980s there was significant experimental support for this idea in the literature (Gensler & Bernstein, 1981. 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 (Bernstein & Bernstein, 1991; Ames & Gold, 1991; Holmes et al., 1992; Rao & Loeb, 1992; Ames et al., 1993).
The DNA damage theory of aging assumes that aging is a consequence of a universal characteristic of life, the vulnerability of the genetic material to damage. Damage in this context means ungoverned chemical reactions that destroy genetic sequence information and/or block replication. In humans, DNA damages occur frequently and enzyme mediated DNA repair processes have evolved to cope with them. On average, about 800 DNA damages occur per hour in each cell, or about 19,200 per cell per day (Vilenchik & Knudson 2000). In any cell some DNA damage may remain despite the action of repair processes. Aging appears to result in large part from the accumulation of unrepaired DNA damages in cells, especially in non-replicating or slowly replicating cells such as those in brain, muscle, liver, kidney and hematopoietic stem cells.
Over the years, the human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter regions in the genome. Genes that are down-regulated over the age of 40 include:
* GluR1 AMPA receptor subunit
* NMDA R2A receptor subunit (involved in learning)
* Subunits of the GABA-A receptor
* Genes involved in long-term potentiation e.g. calmodulin 1 and CAM kinase II alpha.
* Calcium signalling genes
* Synaptic plasticity genes
* Synaptic vesicle release & recycling genes
Genes that are upregulated include:
* Genes associated with stress response and DNA repair
* Antioxidant defence
Normal aging is distinct from Neurodegenerative disease. DNA damage due to oxidation increase as the brain ages, possibly due to impaired mitochondrial function.