Another Win for Senolytics: Fighting Aging at the Cellular Level Just Got Easier

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Manage episode 278459261 series 2515134
By Singularity Hub. Discovered by Player FM and our community — copyright is owned by the publisher, not Player FM, and audio is streamed directly from their servers. Hit the Subscribe button to track updates in Player FM, or paste the feed URL into other podcast apps.
Longevity research always reminds me of the parable of blind men and an elephant. A group of blind men, who’ve never seen an elephant before, each touches a different part of the elephant’s body to conceptualize what the animal is like. Because of their limited experience, each person has widely different ideas—and they all believe they’re right. Aging, thanks to its complexity, is the biomedical equivalent of the elephant. For decades, researchers have focused on one or another “hallmark” of aging, with admirable success. For example, we now know that energy production in aging cells goes haywire. Immune responses ramp up, stewing aging tissue in a soup of inflammatory molecules. Dying cells turn into zombie-like “senescent cells,” where they abdicate their normal functions and instead pump out chemicals that further contribute to inflammation and damage. Yet how these hallmarks fit together into a whole picture remained a mystery. Now, thanks to a new study published in Nature Metabolism, we’re finally starting to connect the dots. In mice, the study linked up three promising anti-aging pathways—battling senescent cells, inflammation, and wonky energy production in cells—into a cohesive detective story that points to a master culprit that drives aging. Spoiler: senolytics, the drug that wipes out senescent cells and a darling candidate for prolonging healthspan, may also have powers to rescue energy production in cells. Let’s meet the players. From Metabolism to Zombie Cells Individual cells are like tiny cities with their own power plants to keep them running. One “celebrity” molecular worker in the process of generating energy is nicotinamide adenine dinucleotide (NAD). It’s got a long name, but an even longer history and massive fame. Discovered in 1906, NAD is a molecule that’s critical for helping the cell’s energy factory, the mitochondria, churn out energy. NAD is a finicky worker that appears on demand—the cell will make more if it needs more; otherwise, extra molecules are destroyed (harsh, I know). As we age, our cells start losing NAD. Without the critical worker, the mitochondria factory goes out of whack, which in turn knocks the cell’s normal metabolism into dysfunction. At least, that’s the story in mice. Although yet unproven for slowing aging or age-related disorders in humans, NAD boosters are already making a splash in the supplement world, raising even more need to understand how and why NAD levels drop as we age. Giving NAD a run for its anti-aging fame are senolytics, a group of chemicals that destroy senescent “zombie” cells. These frail, beat-up cells are oddities: rather than dying from DNA damage, they turn to the dark side, staying alive but leaking an inflammatory cesspool of molecules called SASP (senescence associated secretory phenotype) that “spread” harm to their neighbors. A previous study in ancient mice, the equivalent of a 90-year-old human, found that wiping out these zombie cells with two simple drugs increased their lifespan by nearly 40 percent. Others using a genetic “kill switch” in mice found that destroying just half of zombie cells helped the mice live 20 percent longer, while having healthier kidneys, stronger hearts, luscious fur, and perkier energy levels. Similar to NAD supplements, pharmaceutical companies are investigating over a dozen potential senolytics in a race to bring one to market. But what if we can combine the two? A Hub for Aging The new study, led by aging detectives Drs. Judith Campisi and Eric Verdin at the Buck Institute for Research on Aging in Novato, California, asked if we can connect the line between NAD and zombie cells, like suspects on an evidence board. Their “lightbulb” clue was a third molecule of interest, highlighted in a 2016 study. Meet CD38, a molecule that plays double roles as an aging culprit. It wreaks havoc as an immune molecule to boost inflammation, while chewing up and destroying NAD. If CD38 is a new dru...

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