Mitochondria are the power plants of the cell, a herd of self-replicating structures evolved from ancient symbiotic bacteria, now fully integrated into the cell. Their primary task is the production of chemical energy stores, an energetic process that produces damaging reactive molecules as a side-effect. Much of the original bacterial DNA of the distant ancestors of today's mitochondia has migrated to the cell nucleus, leaving only a tiny remnant genome in the mitochondria themselves. When looking across species with widely divergent life spans, researchers have found good correlations between species life span and some combination of mitochondrial activity (metabolic rate) and mitochondrial composition (how resilient mitochondria are to oxidative damage). This strongly suggests, independently of the copious other evidence, that mitochondria are important determinants of aging and longevity.
There are numerous ways to look at the complexities of the mitochondrial contribution to aging, and until specific repair technologies successfully reverse that contribution, the degree to which different age-related changes in mitochondria are more or less relevant to aging will continue to be a topic of active debate and exploration. In the SENS viewpoint, damage to mitochondrial DNA is most important as a primary cause of aging. It occurs either during replication or as a result of damage from reactive molecules, and can produce mitochondria that are both faulty and able to replicate more readily than their peers. Cells become taken over by broken mitochondria, and become broken themselves, producing a flood of damaged and damaging molecules that contribute to age-related conditions. On the other hand, the more mainstream research community focuses on the general malaise that affects mitochondria in old tissues, characterized by reduced energy store creation, altered dynamics of fusion and fission, and other structural changes. In the SENS view, this is probably a secondary or later consequence of other forms of cell and tissue damage.
Of the two open access papers here, the first is a general, high-level review of mitochondria in aging that paints a picture of a field in flux, moving away from established theories of past decades now proven unhelpful, but not yet entirely sure of the direction for the future. The second examines the topic of how mitochondrial DNA damage originates. There is considerable debate over whether the primary cause is DNA replication errors or the activities of reactive molecules - such as those generated in large amounts by the mitochondria themselves. This paper argues for replication errors to be the important cause, and particularly important in stem cell populations, there contributing to the age-related decline in stem cell activity. The cause of errors, while certainly interesting, is actually not all that relevant to any of the near-term potential methods of repairing or working around the problem. If there is a way to reliably fix mitochondrial DNA in near all cells, or replace it, or provide backup copies of the proteins produced from that DNA blueprint, then it doesn't matter how the damage happened.
On average, a healthy person lives 80 years and one of the highest risk factors known for most human diseases and mortality is aging. Many evolutionary and mechanistic theories have been elaborated on, trying to explain why and how living organisms age. However, from a mechanistic point of view, among all the theories, those that see mitochondria as main actors occupy a particular place. Indeed, mitochondria have been at the center of one leading hypothesis for 50 years: the free radical theory. Even though the scientific community has shifted to a more complex view to explain aging, embracing a network of events, mitochondria remain of high importance because of their central position in cell homeostasis of almost every tissue. Thus, as far as the description of molecular and cellular mechanisms are concerned, mitochondria have been shown to participate in every main aspect of aging: decline of stem cell functions, cellular senescence, "inflammaging," and many others.
Mitochondrial alterations have been extensively described in aging tissues of many organs for a long time. It has been particularly studied in muscle and heart, and sarcopenia and heart failure are two main causes of physical decline in the elderly. In particular, in these two tissues, but also in others like liver, brain and adipose tissue, mitochondrial alterations during aging are multiple. In particular, the number and density of mitochondria, as well as mitogenesis, have been showed to be reduced, whereas for mitochondrial dynamics and content contradictory inconclusive results have been reported. Importantly, mitochondrial function has been regularly reported to be impaired in different aging tissues, in terms of ATP production and respiratory chain (RC) capacity/activity.
A key reported feature of aging mitochondria was the increase in somatic point mutations and large deletions in the mitochondrial DNA (mtDNA). Interestingly, these mtDNA mutations have been shown to be responsible for mitochondrial dysfunction. Since mtDNA is located very close to the major source of reactive oxygen species (ROS), oxidative damage has been considered the main cause of mutations in mtDNA. Indeed, the Mitochondrial Free Radical Theory of Aging (MFRTA) considers the oxidative damage of mtDNA as the primary event affecting RC proteins, inducing its dysfunction and increasing ROS production in a vicious cycle. Yet, this theory has been strongly challenged and the scientific community has had to adjust working hypotheses to fit with a more complex mitochondria-centered network of aging mechanisms.
Besides the nuclear genome, a typical animal cell also has from 100 to 1000 copies of mitochondrial DNA (mtDNA) that encode core subunits of electron transport chain complexes. While converting energy to ATP and carrying out biosynthesis, mitochondria also generate free radicals that can damage DNA, proteins, and lipids nearby. The mitochondrial genome has no histone protection and lacks efficient repair mechanisms. As a result, mtDNA is particularly prone to accumulating mutations. To make matter worse, inefficient electron transport chain (ETC) complexes produced by mtDNA mutations generate more free radicals and exacerbate the mitochondrial damage in a feed-forward cycle.
Accumulation of mtDNA mutations during lifetime has been postulated to cause age-related decline of energy metabolism and impairment of tissue homeostasis. Mitochondrial "mutator" mice with an elevated rate of mtDNA mutagenesis display premature aging, which, in principle, substantiates the correlation between mtDNA mutations and aging. However, mtDNA mutations from various tissues of normally aged human or experimental animals are found to be too low to possibly elicit any pathological consequences, which argues against a causative role of mtDNA mutations in physiological aging, particularly in post mitotic tissues.
DNA replication is a source of mutations. In adulthood, most tissues consist of post mitotic cells that have a slow turnover rate of mitochondria and mtDNA, which might explain the low mtDNA mutation frequency in post mitotic tissues. Therefore, the quest for connection between mtDNA mutations and aging might have focused on the wrong target from the very beginning. On the other hand, one would expect that mtDNA mutations in actively dividing cells, such as cancer cells and stem cells, could reach a high level during the aging process. In fact, there is increasing evidence demonstrating the accumulation of mtDNA mutations in aged stem cells. Stem cells are essential for tissue homeostasis and wound repair. Age dependent deterioration of stem cells contributes to several hallmarks of aging such as impaired capability of tissue repair and increased susceptibility to cancers and infectious diseases, and thereby has been proposed to play an important role in the natural aging process.
In current study, we utilized a physiological approach to manipulate the germline stem cell (GSC) division cycle independently of chronological age in flies, and examine its impact on GSC aging and female reproductive physiology. We demonstrated that the accumulation of division cycles played a major role in maternal age dependent decline of eggs' fitness and contributed to the age dependent decline of female fecundity. Additionally, we detected increased mutations on mtDNA and observed impaired mtDNA replication in aged ovaries. The strong correlation between the decline of stem cell activity and mitochondrial dysfunction in aged ovaries suggests that mtDNA mutations caused by proliferative cycles may contribute to stem cell aging.