Fight Aging!

The hundreds of mitochondria found in every cell are in effect power plants, their primary task being to manufacture the chemical energy store molecule adenosine triphosphate (ATP), which is used to power cellular processes. Mitochondria become damaged like every cellular component, and are recycled frequently. With age, however, changes in expression of mitochondrial and other proteins lead to dysfunctional recycling and dysfunctional mitochondria. ATP production suffers, side-effects of ATP production such as the generation of free radical molecules grow to become problematic, and cell function is impacted. This happens throughout the body, and is thought to be an important contributing cause of degenerative aging.

At least two companies are working earnestly on developing mitochondrial transplantation therapies as a way to treat aging, Mitrix Bio and Cellvie Scientific. Cells will readily take up mitochondria from the surrounding environment. Studies in animals suggest that supplying fully functional mitochondria, harvested from cell cultures, to tissues in which mitochondria are dysfunction can fix the problem for long enough to be interesting as a basis for therapy. The primary challenges are (a) to understand whether mitochondrial haplotypes must match between donor and recipient, (b) cost-effective and reliable manufacture of large enough amounts of undamaged, function mitochondria, and (c) delivery to the harder-to-reach parts of the body. The companies are primarily engaged in the logistics of large-scale manufacture.

Today's open access paper is a compelling demonstration from researchers associated with Cellvie Scientific, demonstrating sizable gains in mitochondrial function, muscle function, and endurance in old mice resulting from direct injection of mitochondria into hindlimb muscles. The amount of mitochondria harvested and injected is reasonable from a manufacturing point of view if scaling up to human use. I expect these companies to initially target frailty, sarcopenia, and related conditions. I also expect the medical tourism community to begin to offer mitochondrial transplantation therapies on much the same timescale. Clinical businesses already have a great deal of experience in managing cell cultures and cell harvesting, and moving from there to harvesting mitochondria is an achievable goal. They have already achieved a similar shift in moving to the use of extracellular vesicles in therapy.

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

Cardiorespiratory fitness is a health indicator of all-cause mortality. One critical component of cardiorespiratory fitness is the function of mitochondria within the skeletal muscle which generates energy to perform exercise or activities of daily living. There is clear evidence that aging results in a reduction in mitochondrial function. Initially proposed as the mitochondrial theory of aging in the 1950s, age-related decreases in mitochondrial function have since been shown to play a major role in skeletal muscle decline. Not surprisingly, in regard to aging-related decline of skeletal muscle, mitochondrial oxidative capacity has been implicated in sarcopenia. Research suggests that the skeletal muscle of elderly individuals exhibits a rise in nonoperational mitochondria, an increase in mutated and deleted mitochondrial DNA with an associated decrease in mitochondrial density.

Non-exercise alternatives such as nutraceuticals or pharmacological agents to improve skeletal muscle bioenergetics act systemically and have resulted in moderate success. Nevertheless, these natural and pharmacological compounds have limitations, particularly in the duration of time (i.e., weeks or months) to induce beneficial molecular and cellular changes in skeletal muscle. Thus, the question arises: "Is there a faster, tissue targeted, and more effective approach to enhance skeletal muscle bioenergetics?"

Mitochondrial transplantation represents a novel therapy designed to enhance energy production of tissues impacted by defective mitochondria. This innovative approach involves transferring isolated mitochondria from either a donor to a host or from the host to itself. Initially used to attenuate the effects of ischemia-reperfusion injury in cardiac tissue transplanted mitochondria, which are rapidly purified and remain viable and capable of respiration, are directly injected into the target tissue. In skeletal muscle, mitochondrial transplantation has proven effective in enhancing hindlimb bioenergetics in various rodent models. Mitochondrial transplantation circumvents the limitations of both exercise and non-exercise interventions by directly delivering isolated mitochondria into the target tissue.

To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. In this study 15 female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice. The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approximately two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.