Mitochondria are the power plants of the cell, packaging chemical energy store molecules to power cellular operations. Mitochondrial function declines with aging, and as one might expect this drags down all aspects of cellular functioning with it. Evidence suggests that this form of degeneration is strongly connected to a failure of the quality control mechanism of mitophagy, which identifies and recycles damaged mitochondria. The proximate cause may be changes in mitochondrial dynamics, particular a diminished amount of fission, the splitting of larger mitochondrial into multiple smaller organelles, leaving too many large and broken mitochondria that cannot be effectively recycled. The connection between this and the known root causes of aging remain obscure.
It is plausible that mitochondrial function is so important to health that some benefit for older individuals can be obtained via forcing greater mitochondrial fission and mitophagy, via changing levels of regulatory proteins, even without addressing the underlying causes. The question at the end of the day is always the size of the effect, of course: even when significant gains are observed in short-lived species, it isn't necessarily the case that this will carry through into long-lived humans. Similarly, upregulating mitochondrial quality control might be far more useful for people with poor lifestyles than for those who have maintained their physical fitness. The research noted here is an example of the standard drug development process applied to the goal of upregulating mitophagy. A natural compound was discovered to boost mitophagy, and after further evaluation was taken into human clinical trials.
During aging, there is progressive decline in the cell's capacity to eliminate its dysfunctional elements by autophagy. Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle. This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individuals. Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health.
Urolithin A (UA) is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mitochondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans, improving mobility and extending lifespan. In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge. Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests.
In this report, we detail the outcome of a first-in-human, randomized, double-blind, placebo-controlled clinical study with UA. We administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.
The present study reveals that UA induces a molecular signature response, in both the plasma and skeletal muscle of humans, resembling that observed as a consequence of a regular exercise regimen. It is important to highlight that our earlier work revealed that the stimulation of mitophagy by UA led to an induction of mitochondrial biogenesis and an enhancement of mitochondrial function, resulting in improved aerobic endurance and higher muscle strength in treated rodents. In humans, endurance exercise is well known to trigger mitochondrial biogenesis and fatty acid oxidation in the skeletal muscle to optimize efficient production of ATP by skeletal muscle cells under aerobic conditions. It has also been shown that exercise is a natural means of triggering mitophagy, making it particularly important to maintain an active lifestyle during aging, as it ultimately results in improved mitochondrial function in the muscle.