Fight Aging!

Cells contain hundreds of mitochondria, constantly fusing together, replicating by splitting apart, and swapping component parts. Mitochondrial function is vital to cell health, and declining mitochondrial function is an important component of degenerative aging. Some of the answers as to why mitochondrial function declines with age are likely buried somewhere in the complex interactions of mitochondrial structure, the dynamics of mitochondrial fusion and fission, and the operation of the mitochondrial quality control processes of mitophagy. Mitophagy is both necessary to maintain function by destroying worn mitochondria, but it also seems quite sensitive to changes in structure and size of mitochondria, as happens when the dynamics of fusion and fission change.

In today's open access paper, researchers demonstrate that compounds that improve the activity of mitofusin, a protein that is important in mitochondrial fusion, lead to improved mitochondrial function and slowed aging in short-lived nematode worms. This is perhaps more interesting than the average result of this nature because at least one mitofusin activator is somewhere in the process of development as a human therapy. Nonetheless, when it comes to modulating mitochondrial dynamics, a survey of the literature will show papers in which benefits arise from inducing greater fission, greater fusion, and greater equilibrium. In short, it is complicated, and one shouldn't take any individual result as promising without looking at contradictions that characterize the broader field of such efforts.

Mitofusin Activation Delays Aging in Caenorhabditis elegans

Age-linked tissue dysfunction is associated with mitochondrial degeneration manifested as organelle fragmentation and respiratory dysfunction. Efforts to mitigate downstream consequences of mitochondrial degeneration, as with reactive oxygen species (ROS) scavengers, have not translated to the human condition. We posit that intrinsic fusion-mediated mechanisms for mitochondrial protection modulate aspects of aging linked to mitochondrial abnormalities. In C. elegans roundworms mitochondrial fusion is mediated by the mitofusin ortholog Fuzzy Onion-1 (fzo-1).

Here, the addition of a mitofusin inhibitor, MFI8, to cultures of age-synchronized C. elegans shortened worm lifespan in a concentration-dependent manner. Reciprocally, the mitofusin activators Chimera and 8015-P2 prolonged worm survival in a dose-dependent manner. The pro-survival effect of Chimera was absent in worms lacking its protein target, FZO-1, and at lower concentrations Chimera-amplified survival was further increased by absence of the mitochondrial fission protein that acts in opposition to fzo-1, DRP-1. The mitofusin activator 8015-P2, which is more potent than Chimera, exhibited greater anti-aging effects on lifespan and improved worm healthspan measured as forced swimming activity and resistance to thermal and oxidative stresses.

These proof-of-concept worm studies identify aging phenotypes reciprocally related to fzo-1/mitofusin activation status. As 8015-P2 is under development for use in human neurodegenerative diseases, it might alleviate aging phenotypes evoked by mitochondrial degeneration in higher species.