Aging is a universal human reality. Concern regarding aging—and a collective aversion to it—has even generated entire industry segments dedicated to anti-aging products, from expensive supplements through pricey lotions. People are afraid of the issues that can come up with advanced age: cancer, cognitive decline, wrinkles and age spots, mobility issues, sexual dysfunction, and any number of other impediments to daily life and ongoing vigor.
Scientists want to understand the way aging is reflected in cells, for two key reasons. These mechanisms can elucidate the contributing factors that lead to diseases like cancer, osteoporosis, and coronary artery disease. Understanding the specific processes that account for how aging occurs can also provide potential points for therapeutic intervention, to counter aging or even prolong lifespans.
One avenue of research involves studying cellular respiration and metabolism. A research team from the University of Tsukuba recently undertook this problem, zeroing in on the effect that aging has on the relationship between epigenetics and the function of mitochondria.
The team focused on serine hydroxymethyltransferase 2 (SHMT2), an enzyme that has been a popular target for anticancer and antimalarial drugs in recent years. SHMT works by converting serine to glycine in a similar mechanism that DNA methyltransferase converts cytosine to 5-methylcytosine.
“In a previous study, we proposed that the age-associated downregulation, or decrease in expression, of nuclear-encoded genes including SHMT2 impacts mitochondrial respiration” noted Haruna Tani, lead author of the study recently published in Scientific Reports. Mitochondrial respiration is a process carried out by these organelles, found in every cell, to release the energy needed to support an organism’s function; this is why mitochondria are informally nicknamed the “powerhouses of the cell”.
Researchers knocked out the SHMT2 gene in mouse embryos and looked at the resulting effects. Interestingly enough, mitochondrial respiration was negatively impacted, limiting growth, all specifically in the liver and not the brain.
This liver disruption in turn affected the production of taurine, which is necessary for successful cell division since it’s needed for mitochondrial respiration as well as for the production of nucleotides.
Senior author Jun-Ichi Hayashi had some insights to contextualize these observations. “Although some researchers have proposed that human aging and age-related defects in mitochondrial respiration are caused by the accumulation of mutations in mitochondrial DNA”—with one of the hallmarks of age-associated defects being that long-term accumulation of defects in DNA—”our data support an alternative explanation: age-related defects in mitochondrial respiration may be triggered by changes in the activity of metabolic pathways that are caused by epigenetic downregulation, but not by mutations, of specific genes associated with mitochondrial function.”
This same research group found mitochondrial defects in fibroblasts harvested from elderly human subjects. They proposed that these changes were the result of epigenetic changes that led to the downregulation of genes like SHMT2 as noted above. What adds a layer of complication to this finding is that, while the temptation might be to start investigating whether administering supplements that upregulate SHMT2 and similar genes could turn around the metabolic slowdowns, SHMT2 is also upregulated in tumor cells.
In these cells, it serves to promote their out-of-control growth. Inactivating SHMT2 and similar genes can therefore help stop tumor growth; doing the opposite could prove catastrophic. And so, researchers need to focus on further elucidating the delicate balances of controls at play—including epigenetic controls, which provide multiple layers of nuanced control to cellular growth and development, in parallel to the permanent traits facilitated by the genetic sequence—in order to identify potential windows for intervention. Perhaps there is an extent to which aging could be slowed down, through epigenetic intervention, without promoting tumor growth, but that will take further study.
Source: Tani H, et al. (2019) Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders Nature Communications10 (193)
Reference: University of Tsukuba “Slowing Down – Is Aging Caused by Decreased Cellular Metabolism?” University of Tsukuba Research News. 20 Nov 2019. Web.