Mitochondrial Dysfunction: Hallmark of Aging #6

We’ve made it to the 6th of the 12 hallmarks of aging: mitochondrial dysfunction! Mitochondrial dysfunction is part of the antagonistic group of hallmarks. They respond to the primary hallmarks—genomic instability, telomere shortening, epigenetic alterations, and loss of proteostasis—or primary causes of cell damage. In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity. At first, at low levels, these responses mitigate the damage caused by the primary hallmarks, but eventually they become harmful themselves.

Meet the Mitochondria

The mitochondria is an important organelle or compartment of the cell. They break down food molecules and produce ATP, the molecular fuel of the cell. Beyond energy production, mitochondria are also central to how cells are put together and die, how they respond to infections and injury, and in the changes that lead to cancer and aging. 

Among the unique features of this organelle are that it has its own DNA and is highly responsive to the cell’s energy needs. By fusing, dividing, and forming extensive networks in the cell—they can respond to changes in energy demand. They can even move within the cell to where the energy need is localized. 

Mitochondrial Dysfunction and Aging 

As cells and organisms age, the efficacy of the respiratory chain—the process by which mitochondria produce ATP—diminishes and less ATP is produced. A theory called mitochondrial free radical theory of aging proposes that due to the dysfunction that occurs with aging, there is also increased production of reactive oxygen species (ROS). Increased ROS in the cell then causes further mitochondrial deterioration and cellular damage more widely.  At first, however, the increase in ROS appears to trigger a stress-elicited survival signal and activate a compensatory response; basically, the increase of ROS triggers the cell to, at first, do better. Beyond a certain threshold, however, the levels of ROS aggravate rather than alleviate the damage. 

Mitochondrial dysfunction is also known to contribute to aging independently of ROS. There are a variety of mechanisms by which this can occur, among them is the reduced ability of mitochondria to form—the dynamic capability discussed above—as a consequence of damage to the mitochondrial DNA. You may recall from Hallmark 2, telomere attrition, that some aging due to DNA dysfunction can be reversed by telomerase activation. Mitochondrial function too has been shown to be partially reversed by telomerase activation; and there is a decent body of evidence to suggest that telomeres help control mitochondrial function and protect against age-associated diseases.

When the mitochondria cannot produce sufficient energy, due to the accumulation of damage and failure to repair, the cell could be pushed into senescence or trigger apoptosis.

Responding to Mitochondrial Dysfunction

The cell can respond to mitochondrial dysfunction in many ways, but we will discuss two: mitohormesis, called hormesis below, and mitophagy, a mitochondria-specific autophagy.

Hormesis is a concept that suggests that mild toxic treatments trigger beneficial compensatory responses. These responses surpass simply repairing the triggering damage and can produce an improvement even when compared to the pre-damaged cell. This explains why, to a point, an increase in ROS improves cell fitness. The pharmaceutical Metformin, for example, a known geroprotector, has been suggested as a low-level mitochondrial poison; the resultant low-energy state (because the mitochondria is functioning less efficiently), activates AMPK and increases lifespan. 

Mitophagy, the mitochondria’s way of taking out the trash, targets deficient or damaged mitochondria for degradation. Interestingly, and perhaps not surprising from what we know about autophagy, fasting  and endurance exercise may improve health span through the capacity to avoid mitochondrial degeneration. The beneficial effects are due, at least in part, to the triggering of mitophagy.

Mitochondrial Dysfunction you can See

Mitochondrial dysfunction and oxidative stress (by ROS) is particularly visible with respect to skin aging. Mitochondria play important roles in skin function; they produce the energy required for important cell processes like signaling, wound healing, pigmentation, vasculature homeostasis, and hair growth. They also help in defense against infection.

Mitochondrial damage, which accumulates due to age and in response to sun and pollutant exposure, is directly linked to skin aging phenotypes: wrinkle formation, hair graying and loss, uneven pigmentation, and decreased wound healing. It’s important to note that many of the mechanisms contributing to skin aging are not fully understood; we can’t tell you exactly why hair thins or grays, for example. But, there are a couple of easy behaviors that can help prevent or mitigate mitochondrial damage: caloric restriction (fasting) and wearing sunscreen.

There is some evidence in animal models that caloric restriction promotes thickening of the epidermis (the top layer of skin) and prevents skin thinning and hair loss, for example. In one experiment, mice that consumed 60% of the diet of the controls for six months had significant vasculature, skin, and fur remodeling. In addition, the mice were healthier and leaner when compared to their peers on multiple points.  

In addition to fasting, protecting the skin from exposure to the sun (and UV radiation) can help prevent mitochondrial damage and its effects. Skin that is exposed to solar light has higher levels of mitochondrial DNA damage, which leads to lower energy production and cellular damage more widely. Using sunscreen regularly on sun-exposed skin can provide a protective layer that prevents damage and wrinkles. 

Protect your Mitochondria

It’s easy to see how mitochondrial dysfunction can contribute to aging, even from just an energy standpoint. If you have less energy, less will get accomplished. This is true for your mitochondria and on Saturday mornings when the to-do list is long. Like most of the hallmarks discussed so far, living healthfully and even introducing regular fasting can address some of the mitochondrial damage associated with aging. And, in the famous words of Baz Luhrmann, “Wear sunscreen. If I could offer you only one tip for the future, sunscreen would be it.”

Written by: Katsume Stoneham, BS, Molecular Biology, MA, Public Health