Every cell contains hundreds of mitochondria, a highly dynamic population of bacteria-like structures responsible for generating the energy store molecule ATP, used to power cellular processes, and that take part in the operation of many of those cellular processes in other ways as well. They are bacteria-like because they evolved from symbiotic bacteria, and still have a remnant of their original DNA. Mitochondria constantly divide, fuse together, are culled by cellular quality control mechanisms, and promiscuously swap their DNA and component parts with one another. Cells even exchange mitochondria. All of this makes mitochondria very challenging to study: they don't stand still to be counted and assessed. Any yet the changes that take place in mitochondria over the course of a lifetime appear very important as a determinant of aging and age-related disease. So difficult or no, the research community must better understand how mitochondria contribute to aging and how that contribution can be turned back.
There are at least two quite distinct classes of process taking place in mitochondria. Firstly there is the damage to mitochondrial DNA that produces dysfunctional mitochondria that can take over cells and make them dysfunctional as well. This involves large deletion mutations, happens as a result of the normal operation of cellular metabolism, and produces a small population of problem cells that pollute the surrounding tissue with oxidized, damaged molecules. This is familiar to those who follow SENS rejuvenation research, as it is here that the recommended intervention takes place: copying mitochondrial DNA into the cell nucleus to provide a backup source of protein machinery to keep the mitochondria from malfunctioning the the harmful way that contributes to the aging process.
The second class of process is much more complex, and involves changes in mitochondrial dynamics of fusion and fission, population size, shape of mitochondria, and energy production. From a SENS point of view, these are secondary and later effects that take place as a consequence of other primary forms of damage and change in aging: cells and their components react, and often in ways that make things worse. All of these mitochondrial changes are comparatively poorly understood as a holistic process, though there are a great many papers that look at thin slices of the issue. Many age-related conditions, particularly neurogenerative conditions as brain cells require a large supply of energy to function correctly, are associated with failing mitochondrial function as a whole: less energy, disrupted participation in cellular activities, and the character of mitochondrial activity changes in numerous other ways.
Some researchers have attempted to classify some of the zoo of possible states of mitochondrial activity in aged tissues by the degree of fusion and fission taking place, by whether mitochondria are becoming fused and large, or staying small in greater numbers. They are also in search of ways to adjust mitochondrial dynamics by dialing up or down the level of fusion or fission. As the research here makes clear that is a very crude starting point when it comes to understanding a complex situation - whether or not changes to fusion and fission map to better or worse outcomes is dependent on other details. I see this as yet more efforts to tinker with the disease state rather than buckling down to strike at the roots of the problem. To make significant progress, tackle the less complex, better understood roots of aging rather than trying to force a partially understood end state into a slightly less worse configuration. This choice of strategy, and the fact that most research groups take the worse approach, is just as apparent in mitochondrial research as it is elsewhere in the field.
Manipulating mitochondrial networks inside cells - either by dietary restriction or by genetic manipulation that mimics it - may increase lifespan and promote health, according to new research. The study sheds light on the basic biology involved in cells' declining ability to process energy over time, which leads to aging and age-related disease, and how interventions such as periods of fasting might promote healthy aging. Mitochondria - the energy-producing structures in cells - exist in networks that dynamically change shape according to energy demand. Their capacity to do so declines with age, but the impact this has on metabolism and cellular function was previously unclear. In this study, the researchers showed a causal link between dynamic changes in the shapes of mitochondrial networks and longevity.
The scientists used C. elegans (nematode worms), which live just two weeks and thus enable the study of aging in real time in the lab. Mitochondrial networks inside cells typically toggle between fused and fragmented states. The researchers found that restricting the worms' diet, or mimicking dietary restriction through genetic manipulation of an energy-sensing protein called AMP-activated protein kinase (AMPK), maintained the mitochondrial networks in a fused or "youthful" state. In addition, they found that these youthful networks increase lifespan by communicating with organelles called peroxisomes to modulate fat metabolism.
"Low-energy conditions such as dietary restriction and intermittent fasting have previously been shown to promote healthy aging. Understanding why this is the case is a crucial step towards being able to harness the benefits therapeutically. Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity."
Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO).
Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.