In Aging Cell, Dr. Vadim Gladyshev and a team of researchers have described how elamipretide beneficially affects mitochondrial pathways and reverses frailty in mice.
A drug on its way to the clinic
As a mitochondria-affecting antioxidant peptide, elamipretide has been, and continues to be, the subject of multiple investigations. As far back as 2004, researchers were testing whether its effects against reactive oxygen species (ROS) had benefits against ischemia-reperfusion injury [1], which occurs when blood is restored to tissue after it has been cut off, such as when a heart attack is treated. Other work has used it to treat heart failure in dogs [2]. Right now, Stealth Biotherapeutics is waiting for the FDA to approve it as a new drug for treating Barth syndrome, a rare mitochondrial disease.
Despite its clinical benefits, it has been little investigated in the context of aging biomarkers. Theoretically, a drug that has significant benefits for people suffering mitochondrial disorders and age-related diseases would similarly improve known biomarkers, such as epigenetic clock measurements and, relatedly, gene expression. These researchers, therefore, attempted to investigate if that is the case.
What elamipretide affects
The first experiment described in this paper tested function in 5-month-old and 24-month-old Black 6 mice, both males and females. Osmotic pumps under the mice’s skin delivered elamipretide for 8 weeks, after which the mice were tested and examined again.
The frailty index, a measurement of flaws in overall physical function that is often used to diagnose age-related weakness, was decreased in older mice of both sexes that had received elamipretide, despite being two months older at the end of the study. Heart function, as measured by ejection fraction and pumping force, was significantly improved. There were also benefits against fatigue, particularly in females.
Multiple molecular pathways received significant benefits. As expected of a drug that treats the mitochondria, many of the affected pathways were related to mitochondria organization and transport along with ATP production and oxygen processing. Immunological pathways that are upregulated with aging were downregulated with elamipretide, suggesting some benefits against inflammaging.
What elamipretide doesn’t affect
The heart enlarges with age, and elamipretide did nothing to ameliorate this. The mass of the gastrocnemius, a crucial muscle in the leg, was unaffected. Despite its effects on frailty, it did not appear to have consistently significant effects on overall skeletal muscle force; it appeared to increase maximum force in older female mice while decreasing maximum force in older male mice.
Most interestingly, despite the effects on pathways, there were no effects on differentially expressed genes related to aging. Aging clocks, including transcriptomic clocks and the Horvath epigenetic clock, were used on multiple tissues, and none of them revealed any difference; the old treated mice, despite being significantly less frail, did not become biologically younger. While there appeared to be trends towards gene expression that are similar to the effects of rapamycin, these findings were not statistically significant.
Similarly, although there were a couple of findings involving effects on cap-independent translation targets, which are alternate metrics of longevity, the researchers hold that these unclear results were largely negligible and that elamipretide does not, overall, have significant effects on molecular longevity predictors.
This study sheds light on the difference between functional benefits and biomarker metrics, potentially revealing the limitations of clocks. Elamipretide may have no benefits against epigenetic aging, but it has clear benefits for the mitochondria, and it is poised to reach the clinic. Further clinical determinations will reveal if it is effective against frailty in human beings.
Literature
[1] Zhao, K., Zhao, G. M., Wu, D., Soong, Y., Birk, A. V., Schiller, P. W., & Szeto, H. H. (2004). Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry, 279(33), 34682-34690.
[2] Sabbah, H. N., Gupta, R. C., Kohli, S., Wang, M., Hachem, S., & Zhang, K. (2016). Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circulation: Heart Failure, 9(2), e002206.
