01 October 2020

Cellular cannibalism and aging

Researchers from the Perelman School of Medicine at the University of Pennsylvania have shown how autophagy (the cellular process of self-digestion in lysosomes) causes the SIRT1 enzyme to decompose in cells and tissues in old mice.

SIRT1 is known to play an important role in longevity. Blocking its autophagy may be a potential approach to restoring SIRT1 levels in patients and treating or preventing age-related disorders of organs and systems. The results are particularly interesting for the study of aging of the immune system.

The role of SIRT1 autophagy in immune cells is a concept that has not been studied before. To determine the mechanism of SIRT1 loss during aging, the researchers first excluded causes such as mRNA synthesis and stability – important factors in controlling gene expression. For this purpose, methods of sequencing mouse cell RNA were used. During further experiments, the researchers found that disabling the autophagy-related Atg7 protein in aging cells led to the preservation of SIRT1 expression at a "young" level. This proves that the main role in the loss of SIRT1 and aging belongs to the process of autophagy, and not to proteasomes – another processing factory in the body. Immunofluorescence staining showed that LC3, another protein responsible for autophagy, also causes the loss of SIRT1 in aging cells and tissues.

Studies in mice have also proven the role of autophagy in aging. The proteasome inhibitor, which blocks the breakdown of proteins in the cell, was unable to restore the level of SIRT1 in aging cells and tissues, while treatment with Lys05, which is a lysosomal inhibitor of autophagy, reduced the loss of SIRT1, confirming that the enzyme is decomposed by lysosomes.

To determine the role of autophagy in immune cells, the researchers treated human CD8 T lymphocytes with small doses of Lys05 and a proteasome inhibitor and found that only Lys05 increased SIRT1 levels.

Thus, during the aging of human T cells, SIRT1 degrades, at least partially, through autophagy, a mechanism that can influence the reprogramming of aging immune cells.

Next, the researchers plan to further study the interaction of LC3 and SIRT1 in preclinical studies and describe in more detail the signaling pathway for finding targets to block it. Stabilization of the SIRT1 protein level by interrupting this interaction may become a new direction in the development of anti-aging therapy.

Article by C.Xu et al. SIRT1 is downregulated by autophagy in senescence and aging published in the journal Nature Cell Biology.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert: Blocking enzyme's self-destruction process may mitigate age-related diseases.

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