Aging

A number sign (#) is used with this entry because aging represents a phenotype seemingly related to changes in mitochondrial DNA.

Description

Progressive damage to mitochondrial DNA (mtDNA) during life is thought to contribute to aging processes. This notion is supported by the observation of an aging-related accumulation in human mtDNA of oxidative and alkylation derivatives of nucleotides, of small deletions and insertions, and of large deletions, although their low frequency raises questions about their functional significance (Michikawa et al., 1999).

Molecular Genetics

Bittles (1992) and Wallace (1992) discussed the possible role of mtDNA mutation in aging related to the decline in oxidative phosphorylation. Harding (1992) raised the question of whether growing old is the most common mitochondrial disease.

Corral-Debrinski et al. (1992) investigated 7 brains from subjects aged 24 to 94 years, and specifically amplified mtDNA harboring 2 different large deletions from different brain regions. Deleted mtDNA was barely detectable in the youngest subject, but the ratio of deleted to normal mtDNA increased with age, particularly over the age of 80 years. The increase was most striking in the putamen and minimal in the cerebellum.

Soong et al. (1992) reported essentially similar observations in 6 brains, but studied more brain regions. Deleted mtDNA was most abundant in the substantia nigra, also present in relatively large amounts in the striatum, but, again, scarce in the cerebellum. They pointed out that gray matter regions contained the most deleted mtDNA, suggesting that it accumulated preferentially in neurons rather than in glial cells.

Simonetti et al. (1992) used a quantitative PCR technique to measure the amount of a specific mtDNA deletion in human tissues at various ages. They used the deletion of nucleotide pair 4977, which is called the 'common deletion' because it has been found in about one-third of all Kearns-Sayre syndrome patients (530000). By this method, they estimated that there is a 10,000-fold increase in the deleted mtDNA species in muscle during the course of the normal human life span. The maximum amount of common deletion observed in aged muscle was approximately 0.1%. Tissues that turn over slowly, such as skeletal muscle and heart, contained more of the deleted species than more rapidly dividing tissues, such as liver.

Tanaka et al. (1998) reported that a mitochondrial 5178C-A transversion, which results in a met-to-leu substitution in the MTND2 gene (516001), was found much more frequently in Japanese centenarians than in blood donor controls. The authors postulated that certain mitochondrial mutations may protect against development of adult-onset diseases. Mitochondrial DNA polymorphisms associated with longevity were described in a Finnish population by Niemi et al. (2003).

Michikawa et al. (1999) described high-copy point mutations at specific positions in the control region for replication of human fibroblast mtDNA from normal old, but not young, individuals. Furthermore, in longitudinal studies, 1 or more mutations appeared in an individual only at an advanced age. Some mutations appeared in more than 1 individual. Most strikingly, a T-to-G transversion at nucleotide 414 (414T-G) was identified, in a generally high proportion (up to 50%) of mtDNA molecules, in 8 of 14 individuals above 65 years of age (57%), but it was absent in 13 younger individuals. The 414T-G transversion occurred in the middle of the promoter for mtDNA H-strand replication primer synthesis and L-transcription, at a position immediately adjacent to a segment with high affinity for mitochondrial transcription factor A (TFAM; 600438). Other specific mutations observed in old individuals occurred at positions critical for mtDNA replication, in particular, either in the coding sequence of the RNA primer for H-strand synthesis, within TFAM-binding segments, or very close to the O(H1) primary site or to the O(H2) secondary site of DNA synthesis initiation.

Michikawa et al. (1999) found that in vitro fibroblast populations carrying the heteroplasmic 414T-G mutation showed an outgrowth of the mutant cells. This observation supported the finding that the mutation accumulation is an in vivo phenomenon, while at the same time indicating intrinsic physiologic differences between mutant and wildtype cells. Subcloning experiments revealed a striking mosaic distribution of the mutation.

Wang et al. (2001) observed that biopsied or autopsied human skeletal muscle showed the absence or minimal presence of the 414T-G fibroblast mtDNA mutation. In contrast, the aging-dependent accumulation of 2 novel mutations, an A-to-G transition at nucleotide 1489 (1489A-G) and a T-to-A transversion at nucleotide 408 (408T-A), which were virtually absent in fibroblasts, and in a few individuals tested, also in other tissues, was detected in the muscle of most of 30 individuals aged 53 to 92 years. These 2 novel mutations, which occurred in the same critical sites for mtDNA replication shown to be targeted by the mutations in fibroblasts, were absent or marginally present in 23 individuals younger than 40 years.

By large-scale screening of the mtDNA main control region in leukocytes from subjects in an Italian population, Zhang et al. (2003) identified a homoplasmic C-to-T transition at nucleotide 150 (150C-T) near an origin of heavy mtDNA-strand synthesis in about 17% of 52 subjects aged 99 to 106 years, but, in contrast, in only 3.4% of 117 younger individuals (P of 0.0035). Among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins aged 60 to 75 years, 30% (P of 0.0007) and 22% (P of 0.011), respectively, of the individuals involved exhibited the homoplasmic 150C-T mutation. In 5 human fibroblast longitudinal studies, convincing evidence for the aging-related somatic expansion of the 150C-T mutation, up to homoplasmy, was obtained. The 5-prime end analysis of nascent heavy mtDNA strands consistently revealed a novel replication origin at position 149, substituting for that at 151, only in 150C-T mutation-carrying samples of fibroblasts or immortalized lymphocytes. Considering the age-related health risks that the centenarians had survived and the developmental risks of twin gestations, Zhang et al. (2003) proposed that selection for a remodeled replication origin, inherited or somatically acquired, provides a survival advantage and underlies the observed high incidence of the 150C-T mutation in centenarians and twins.

Lu et al. (2004) showed that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport, and mitochondrial function. This is followed by induction of stress response, antioxidant, and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, Lu et al. (2004) concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory, and neuronal survival, initiating a program of brain aging that starts early in adult life.

Bahar et al. (2006) tested for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. Dolle et al. (2000) and Dolle and Vijg (2002) had demonstrated an increased load of genome rearrangements and other mutations in the hearts of aged mice. To confirm that increased stochasticity of gene expression could be a result of increased genome damage, Bahar et al. (2006) treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at a lacZ reporter locus. Bahar et al. (2006) concluded that their results underscored the stochastic nature of the aging process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.

Scaffidi and Misteli (2006) showed that the same molecular mechanism responsible for Hutchinson-Gilford progeria syndrome (HGPS; 176670) is active in healthy cells, implicating lamin A (150330) in physiologic aging.

Armanios et al. (2009) generated wildtype mice with short telomeres. In these mice, Armanios et al. (2009) identified hematopoietic and immune defects that resembled those present in patients with dyskeratosis congenita (see 305000). Patients with dyskeratosis congenita have a premature aging syndrome that can be caused by mutations in the RNA or catalytic component of telomerase (see TERC, 602322 and TERT, 187270). When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wildtype mice with short telomeres still displayed degenerative defects. Armanios et al. (2009) concluded that their findings implicated telomere length as a unique heritable trait and demonstrated that short telomeres are sufficient to mediate the degenerative defects of aging.