An Open Longevity seminar debated the root cause of aging: Pyotr Lidsky called “damage” an unscientific term, and one speaker reported that a substance that activates the CD74 protein increased “biological age” in mice, as estimated from gene activity

An Open Longevity seminar debated the root cause of aging: Pyotr Lidsky called “damage” an unscientific term, and one speaker reported that a substance that activates the CD74 protein increased “biological age” in mice, as estimated from gene activity

An online seminar took place on October 27 with support from Open Longevity, which Ukhvat is also part of. Lidsky, a coauthor of the hypothesis that aging is part of the immune defense against chronic infections, invited José Pedro Castro of the University of Porto and Matthew Yousefzadeh of Columbia University.

Castro noted that blocking IL-11, a cytokine (an immune signaling protein), extended lifespan in mice, while in zebrafish, this protein is needed for tissues to regenerate without scarring. “The same cytokine can be a villain or a superhero, depending on the context,” he said. He proposed maintaining “inflammatory precision,” with inflammation that helps tissues regenerate predominating over inflammation that leaves scars, rather than suppressing inflammation altogether. He suggested that scarring closes wounds quickly: this helps while the body is young, but scars accumulate over time and cause harm.

Inflammation is usually studied in terms of its association with age; Castro sought a sequence of inflammatory signals whose activation increases biological age. His group applied a “clock,” a model that estimates age from gene activity, to individual cells, identified cells whose age could be explained by inflammation, and selected CD74 from the inflammatory genes these cells shared. CD74 encodes a receptor for an inflammatory signal. Castro reported that mice received four injections of a substance that activates CD74 over a month, with different doses tested; at one dose, the “clock” showed an increase in biological age.

Yousefzadeh described the immune system as a driving force in the spread of aging between organs: its cells circulate throughout the body and detect signals from tissues. He described experiments in which the DNA repair gene ERCC1 was switched off in different tissues. In forebrain neurons, this caused brain atrophy while leaving other organs unaffected; in blood-forming cells (a 2021 Nature paper on which he was the first author), it caused the immune system to age first, followed by signs of aging in other organs. “Aging immune cells make the body accumulate more trash while losing their own ability to take it out,” Yousefzadeh joked.

“I think ‘damage’ is simply an unscientific term. We should either specify what we mean, such as the DNA damage response pathway or a particular defect, or stop using it,” Lidsky said. He explained that when the cause is known, such as a virus that affects the brain, the word “damage” is unnecessary; in aging, the cause remains unidentified, and “damage” has taken its place. In his view, reprogramming that rejuvenates cells and tissue replacement will not help with diabetes, infections, or autoimmune diseases because they leave the cause intact: high blood sugar and autoimmune reactions will kill the new tissues, and infections will reestablish themselves in previously infected tissues.

“Something similar could happen with aging, because we do not understand what is happening.”

Castro proposed defining damage as anything that disrupts a cell’s or tissue’s function and agreed with Lidsky that reprogramming would not help once disease had developed. This makes it necessary to identify stages of accelerated aging earlier.

Worms age without circulating immune cells. Whether immune cells or the tissue itself initiates aging remains unknown, Castro said; his own view favors a loss of identity in tissue cells, for example, a liver cell beginning to behave like a skin cell.