A study published in Aging Cell has reported that older people with better regulated autophagy in their skeletal muscles have less age-related frailty.
Taking out the trash
The researchers begin this paper by discussing the various activities and effects of autophagy. Obviously, too much autophagy is not good, as it aggravates tissue degeneration [1], but a lack of it has also been found to lead to degeneration [2]. The energy-sensing AMPK pathway encourages autophagy, and the related nutrient-sensing mTOR pathway discourages it [3].
There are also multiple types of autophagy, depending on the particular organelle being consumed. Like many things in biology, the full biochemical pathways involved in autophagy have not been entirely mapped out. This work focuses principally on mitophagy, the removal of damaged mitochondria, which is chiefly regulated by PGC-1α [4].
Comparing physical abilities to RNA
After screening, a total of 575 participants, with an average age of 75.9 years, were inducted into this study. Most participants were of European descent, slightly over half were female. Over a third had only one chronic condition, while roughly a sixth had more than one.
A total of 260 genes were chosen for RNA sequencing analysis, based on their roles in autophagy, mitophagy, and/or the mTOR pathway. These genes were checked against key functional metrics, such as mitochondrial function as measured by oxidative phosphorylation (OXPHOS), oxygen consumption, and 400-meter walking speed.
The expression of genes that are central to autophagy machinery were uncorrelated with these outcomes. However, some regulatory genes, such as FoxO1, were found to be significantly negatively correlated, to the researchers’ surprise. Other metabolic regulators were found to have positive correlations, as were genes related to mitochondrial fusion and fission. Some genes related to the mTOR pathway were negatively associated, while others were positively associated.
Unsurprisingly, more OXPHOS was associated with more expression of the sirtuin genes SIRT5 and SIRT3. Multiple mitochondria-related genes were also associated with better oxygen consumption. mTOR and its pathways were associated with better walking speeds.
A potential explanation for contradictory results
Some of these findings are entirely expected. However, some of them, particularly the relationship of more FoxO1 to worse outcomes, goes against a consensus that suggests benefits from this autophagy regulator. These researchers suggest that its upregulation could be a consequence, rather than a cause, of autophagic dysregulation. Increased expression of regulatory genes suggests a need for more regulation, with the body engaging in more quality control in an attempt to compensate.
These results also suggest that inhibiting the effects of mTOR, which naturally inhibits autophagy and is itself inhibited by rapamycin and rapalogs, is a potential path to increased muscle performance in older people. Research in this area has been previously conducted [5], and this paper offers more insight into how such an approach might work.
Literature
[1] Mammucari, C., Milan, G., Romanello, V., Masiero, E., Rudolf, R., Del Piccolo, P., … & Sandri, M. (2007). FoxO3 controls autophagy in skeletal muscle in vivo. Cell metabolism, 6(6), 458-471.
[2] Masiero, E., Agatea, L., Mammucari, C., Blaauw, B., Loro, E., Komatsu, M., … & Sandri, M. (2009). Autophagy is required to maintain muscle mass. Cell metabolism, 10(6), 507-515.
[3] Jung, C. H., Ro, S. H., Cao, J., Otto, N. M., & Kim, D. H. (2010). mTOR regulation of autophagy. FEBS letters, 584(7), 1287-1295.
[4] Vainshtein, A., Desjardins, E. M., Armani, A., Sandri, M., & Hood, D. A. (2015). PGC-1α modulates denervation-induced mitophagy in skeletal muscle. Skeletal muscle, 5, 1-17.
[5] Bodine, S. C. (2022). The role of mTORC1 in the regulation of skeletal muscle mass. Faculty Reviews, 11.
