This article is part of a series on recent advances in the science and medicine of longevity.
Cells, like us humans, grow old with time. As they do, they begin to secrete inflammatory molecules. A little inflammation is important for wound healing and for fighting infections, but it needs to be “turned off” again afterward, otherwise it begins to damage the very thing it set out to heal. Why old cells cause inflammation is not fully understood. Now, researchers at the University of Glasgow and at the Mayo Clinic may have found an answer. Their work, published in Nature, highlights the delicate dance between old cells, inflammation, and mitochondrial DNA: in old cells, mitochondria begin to “leak” their DNA, triggering an immune response and inflammation. Blocking the leak cuts down inflammation.
Cell Division and Cell Senescence
Over time, our cells may get damaged or stressed. This wears on their ability to perform their usual functions. To bypass this issue, cells undergo a process called cell division: they split themselves into two identical “daughter” cells. These daughter cells are fresh and ready for the trials of the world, taking over where their parent cell left off. The old cell is then disposed of by our immune system, having completed its job. Eventually, the daughter cells become parent cells themselves and divide again as needed. And again. And again.
The average human cell can undergo up to 50 or 60 such cell-division cycles. After that, it’s game over. Old cells that have reached their division limit are called “senescent” cells. Although they can no longer divide, they are still metabolically active, often releasing a steady stream of inflammatory molecules — a state called senescence-associated secretory phenotype (SASP). Where usually our immune system swoops in to clear damaged and dysfunctional cells, it struggles to clear senescent cells. They manage to evade elimination, and all the while inflammation continues. As we age, our immune system becomes worse and worse at clearing senescent cells.
Chronic, low-level inflammation —or “inflammaging”— has long been considered a hallmark of aging and has been associated with a range of age-related diseases, including cancer, heart disease, arthritis, and various neurological conditions. Finding a way to eliminate or curb the inflammation that comes with cell senescence could potentially help increase longevity and improve health into old age.
“Minority MOMP”: A Key Piece of the Puzzle
Mitochondria are the power plants of our cells. They help produce the energy needed for virtually all cellular processes and functions. They also have their very own form of DNA, different from that found in the nucleus of the cell; it is circular rather than linear and uses a slightly different genetic code to the universal genetic code employed by nuclear DNA. So-called mitochondrial DNA (mtDNA) is critical to the smooth functioning of mitochondria. It helps provide some of the key ingredients for the production of useable energy.
Mitochondria also happen to be major regulators of the senescence-associated secretory phenotype (SASP) mentioned above. The exact mechanism of this regulation, however, remained unclear. Stella Victorelli, Hanna Salmonowicz, and James Chapman —lead authors of the study— homed in on one potential culprit: mitochondrial outer membrane permeabilization (MOMP). This is a strategy used by mitochondria to help facilitate controlled cell death, or “apoptosis”. In brief, the mitochondrion releases a protein, called cytochrome c, through its membrane and into the cytoplasm of the cell. Like a falling domino, this protein goes on to trigger a number of downstream events that eventually lead to the cell being broken apart and being disposed of.
In the case of senescent cells, there seems to be a breakdown of this process. The researchers discovered that they are instead characterized by a kind of “minority MOMP” (miMOMP). Essentially, some of the mitochondria in the cell begin to undergo outer membrane permeabilization while others do not. The end result is an extended in-between phase of inflammation: too little MOMP to cause cell death, but too much MOMP to allow for healthy functioning of the cell.
The team of scientists noticed that, in senescent cells undergoing outer membrane permeabilization, mitochondrial DNA “leaks” into the cytoplasm of the cells. This misplaced DNA causes alarm bells to ring, leading to the activation of a major mediator of inflammation, known as the cGAS–STING signaling pathway.
Blocking MOMP Reduces Inflammation
Having isolated one of the mechanisms behind the senescence-associated secretory phenotype (SASP), the researchers set out to intervene. They treated aged mice with BAI1, a small-molecule drug known to inhibit mitochondrial outer membrane permeabilization (MOMP). Treatment helped prevent the leakage of mitochondrial DNA and, by extension, curbed the inflammation associated with cell senescence. This had a number of beneficial knock-on effects. For one, the treated mice were less likely to be affected by declining neuromuscular coordination, frequently seen in mice their age — their balance was better and their grip stronger. Treated mice also displayed improved bone “microarchitecture”, with better resistance to torsion and fewer pro-inflammatory proteins. Crucially, this decrease in inflammatory factors extended to the brain, with a noticeable decrease in senescence markers in microglia and oligodendrocytes, two important cell types of the brain.
Mitochondrial outer membrane permeabilization (MOMP) is a key characteristic of controlled cell death, or apoptosis. When it functions as intended, it helps the body get rid of damaged or stressed cells, all while minimizing any unnecessary immune response. This new research shows that senescent cells —which are old cells that can no longer divide— are prone to “minority” mitochondrial outer membrane permeabilization (miMOMP). As a result, instead of senescent cells being broken down, they end up in a state between life and death, triggering low-level inflammation all the while. Blocking MOMP in senescent cells helps prevent inflammation, leading to improved health.
The role of the mitochondria in inducing aging via inflammation is yet another (of many) dysregulations associated with aging. In due time, this new understanding will lead to drugs that slow the process. That, together with knowledge of other pathways that go awry as we age, will lead to longer, healthier lives.