Mitochondria are the power plants of the cell, a herd of cell components evolved from symbiotic bacteria that are responsible for generating energy supplies to power cellular processes, among other tasks. Mitochondria are important in aging, and their dysfunction is involved in many age-related conditions; that much is the consensus in the scientific community. After that, however, there is much ongoing debate and a rapid generation of new papers when it comes to the details of what exactly it is that matters, which aspect of age-related mitochondrial changes are most important, and what the various chains of cause and consequence look like.
There are numerous different research perspectives to muddy the waters, of course. Not every wise man is looking at the same part of the elephant. For example, scientists primarily interested in slowing aging via some form of drug-based therapy tend to look at mitochondria and aging through the lens of cellular housekeeping and mitohormesis. In some genetic or other interventions shown to extend healthy life spans in laboratory species, mitochondria emit more reactive molecules in the course of supplying the cell with stored chemical energy, which causes cells to react with greater housekeeping efforts - and the result is a net gain in reduction of damage. There are other perspectives, however, leading on from variants of the mitochondrial free radical theory of aging in which mitochondrial DNA damage is seen as the start of a chain of consequences that leads to malfunctioning cells. Mitochondria need the right protein building blocks in order to function, and if the genes encoding those proteins are broken, then failures begin to occur. Some of the SENS rejuvenation research programs follow on from that theory, and so attempt to ensure that even with DNA damage, the proteins will be available. There are other potential approaches to repair and workaround as well.
These are not the only viewpoints. Many researchers have very narrow interests in mitochondrial function with respect to one specific age-related condition, and are focused down on that one thin slice of biochemical complexity. Then there are those scientists who work to catalog natural variations in longevity and their genetic causes, engaged in identifying a contribution caused by different mitochondrial haplogroups through surveys of population data. Were scientists more minded towards intervention this could be the starting point on the road to developing a better set of mitochondrial DNA, an improved, optimized version that could be provided via gene therapy. Not as important as learning how to fix the set of mitochondrial DNA we have, of course: it doesn't much matter that your engine is more fuel-efficient if you still cannot repair it.
But you get the picture. Mitochondria research is a very active field, with a lot of different goals, interests, and back and forth at the cutting edge. New data arrives on a weekly basis, and always something in there to disagree with. Here is a small collection of some recent papers, which should give you an insight into how things go in this slice of aging research.
Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases.The Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. The hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy.
The importance of mitochondrial biology as a trait d'union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics. Mitochondria could play a key role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging.
In the last century, considerable efforts were made to understand the role of mitochondrial DNA (mtDNA) mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle.
New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.
Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan.
Interest in mitochondrial influences on extended longevity has been mounting, as demonstrated by a growing literature. Such work has demonstrated that some haplogroups are associated with increased longevity and that such associations are population-specific. Most previous work however, suffers from the methodological shortcoming that long-lived individuals are compared with "controls" who are born decades after the aged individuals were. The only true controls of the elderly are people who were born on the same time period, but who did not have extended longevity. Here we present results of a study in which we are able to test if longevity is independent of haplogroup type, controlling for time period, by using mitochondrial DNA genealogies. Since mtDNA does not recombine, we know the mtDNA haplogroup of the maternal ancestors of our living participants. Therefore, we compare the haplogroup of people with and without extended longevity, who were born during the same time period.
Our sample is an admixed New World population which has haplogroups of Amerindian, European and African origin. We show that women who belong to Amerindian, European and African haplogroups do not differ in their mean longevity. Therefore, to the extent that ethnicity was tied in this population to mtDNA make up, such ethnicity did not impact longevity. In support of previous suggestions that the link between mtDNA haplogroups and longevity is specific to the population being studied, we found an association between haplogroup C and decreased longevity. Interestingly, the lifetime reproductive success and the number of grandchildren produced via a daughter of women with haplogroup C are not reduced. Our diachronic approach to the mtDNA and longevity link allowed us to determine that the same haplogroup is associated with decreased longevity during different time periods, and allowed us to compare the haplogroup of short and long-lived individuals born during the same time period. By controlling for time period, we minimize the effect of different cultural and ecological environments on differential longevity. With our diachronic approach, we investigate the mtDNA and longevity link with a biocultural perspective.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death.
On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders.
Association between amyloid-β (Aβ) toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage has been demonstrated in the pathophysiology of Alzheimer's disease (AD). In the early stages of the disease, the defect in energy metabolism was found to be severe. This may probably due to the Aβ and ROS-induced declined activity of complexes in electron transport chain (ETC) as well as damages to mitochondrial DNA. Though clinically inconclusive, supplementation with antioxidants are reported to be beneficial especially in the early stages of the disease. A mild to moderate improvement in dementia is possible with therapy using antioxidants.
Since mitochondrial dysfunction has been observed, a new therapeutic strategy called 'Mitochondrial Medicine' which is aimed to maintain the energy production as well as to ameliorate the enhanced apoptosis of nerve cells has been developed. Mitochondrial CoQ10, Szeto-Schiller peptide-31 and superoxide dismutase/catalase mimetic, EUK-207 were the mitochondrial targeted agents demonstrated in experimental studies. This article discusses the mitochondrial impairment and the possible mitochondria targeted therapeutic intervention in AD.
That last one is interesting for related reasons: it seems that efforts to selectively target antioxidants to mitochondria continue to spread on the basis of promising early results from some lines of development published over the past decade or so. There's a post back in the Fight Aging! archives on Szeto-Schiller peptide-31, and many of you probably know about the development of plastiquinones such as SkQ1.