Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.
As we age, our cells undergo various changes, and one significant factor is the accumulation of damage to our DNA. This damage often leads to cellular senescence, a state where cells stop dividing and can contribute to aging-related issues. A crucial cellular process called autophagy, which acts like a cellular recycling system, normally helps to clear out damaged components and maintain cell health. This research sheds light on how aging-related shifts in our metabolism influence this vital recycling process. The scientists discovered an elevated level of a protein called DNA damage regulated autophagy modulator 1 (DRAM1) and a specific type of autophagy, which they termed DRAM1-mediated pro-senescent autophagy (DMPA), in aging stem cells from human umbilical cords and in the livers of mice. They found that this particular type of autophagy is closely linked to alterations in how cells process nutrients. Specifically, the accumulation of two metabolic byproducts, N-acetylhistamine and phosphatidylethanolamine, was found to promote this aging-related autophagy. N-acetylhistamine, in particular, was shown to increase DNA damage and enhance DMPA. While phosphatidylethanolamine also boosted autophagy, its role in directly causing DNA damage and senescence was less pronounced unless combined with N-acetylhistamine. A key part of the mechanism involves DRAM1 activating an important cellular energy sensor called AMPK. Interestingly, this specialized autophagy (DMPA) behaves differently from general autophagy; it doesn’t significantly reduce certain proteins (like SQSTM1/p62) that are usually involved in packaging cellular waste for degradation. This suggests a unique way this process handles cellular cleanup during aging. By understanding these specific metabolic and molecular pathways that drive DMPA, researchers hope to develop new strategies to help cells repair DNA and potentially slow down the aging process.