Enhancing cellular clearance in neurons derived from older donors' skin cells shifted some mitochondrial measures toward younger levels
Enhancing cellular clearance in neurons derived from older donors' skin cells shifted some mitochondrial measures toward younger levels
On August 16, 2026, Eva Klinman and colleagues published a study of cortical neurons produced by directly converting skin cells from people of different ages. In neurons from older donors, the acidic stage of autophagy, the process by which cells clear damaged components, was less active. When the authors increased the formation of autophagosomes, the vesicles involved in this clearance, some mitochondrial measures shifted toward the levels seen in younger cells.
Neurons have long processes, and material requiring degradation can arise far from the cell body. Autophagy encloses damaged components in vesicles called autophagosomes. Lysosomes, which are vesicles containing enzymes, fuse with autophagosomes, create an acidic environment, and break down the material inside. For autophagosomes to become acidic within long neuronal processes, lysosomes must reach the sites where this material accumulates.
Neurons in older people are difficult to observe in living tissue. The authors therefore converted fibroblasts, connective tissue cells from the skin, into cortical neurons. This conversion bypassed the intermediate stage that erases cellular signs of age, so the resulting neurons retained the donor's age-related features. The authors compared cell lines from younger and older donors, as well as six pairs of samples collected from the same men about 15 years apart.
In older cells, 16.64% of autophagosomes became acidic, compared with 47.06% in younger cells. The processes of older neurons contained fewer lysosomes. The electrical potential across the inner mitochondrial membrane was lower, while mitochondrial division and fusion occurred more often.
The authors interpret these findings as a single sequence of events. A shortage of lysosomes in neuronal processes prevents autophagosomes from becoming acidic. As a result, mitochondria divide and fuse more often, which allows them to exchange components. The authors propose that this response helps cells maintain mitochondrial function when damaged components are cleared less efficiently.
In the full text of the same study, the authors tested this proposed sequence using G2-115, a compound that increases autophagosome formation. The number of autophagosomes in neuronal processes increased by 60% across all age groups. In six donor cell lines from people older than 65 years, the proportion of acidified autophagosomes and the number of vesicles containing mitochondrial fragments increased. The electrical potential across the inner mitochondrial membrane rose to the level found in younger cells, while mitochondrial division and fusion became less frequent. Lysosomes nevertheless remained scarce in neuronal processes.