How Targeting ‘Zombie Cells’ Could Help Extend Healthspan

What if a drug could help you live a longer, healthier life?
Scientists at the University of Connecticut are working on it. In a new study in Cell Metabolism, researchers described how to target specific cells to extend the lifespan and improve the health of mice late in life.
The study builds on a growing body of research, mostly in animals, testing interventions to slow aging and prolong healthspan, the length of time that one is not just alive but also healthy.
“Aging is the most important risk factor for every disease that we deal with in adult human beings,” said cardiologist Douglas Vaughan, MD, director of the Potocsnak Longevity Institute at Northwestern’s Feinberg School of Medicine, Chicago. (Vaughan was not involved in the new study.) “So the big hypothesis is: If we could slow down aging just a little bit, we can push back the onset of disease.”
As we age, our cells wear out. It’s called cellular senescence — a state of irreversible cell cycle arrest — and it’s increasingly recognized as a key contributor to aging.
Senescent cells — or “zombie cells” — secrete harmful substances that disrupt tissue functioning. They’ve been linked to chronic inflammation, tissue damage, and the development of age-related diseases.
Senescence can be characterized by the accumulation of cells with high levels of specific markers like p21, or p21high cells. Almost any cell can become a p21high cell, and they accumulate with age, said Ming Xu, PhD, a professor at the UConn Center on Aging, UConn Health, Farmington, Connecticut, who led the study.
By targeting and eliminating p21high senescent cells, Xu hopes to develop novel therapies that might help people live longer and enjoy more years in good health.
Such a treatment could be ready for human trials in 2-5 years, Xu said.
What the Researchers Did
Xu and colleagues used genetic engineering to eliminate p21high cells in mice, introducing into their genome something they describe as an inducible “suicide gene.” Giving the mice a certain drug (a low dose of tamoxifen) activated the suicide gene in all p21high cells, causing them to die. Administering this treatment once a month, from age 20 months (older age) until the end of life, significantly extended the rodents’ lifespan, reduced inflammation, and decreased gene activity linked to aging.
Treated mice lived, on average, for 33 months — 3 months longer than the untreated mice. The oldest treated mouse lived to 43 months — roughly 130 in human years.
But the treated mice didn’t just live longer; they were also healthier. In humans, walking speed and grip strength can be clues of overall health and vitality. The old, treated mice were able to walk faster and grip objects with greater strength than untreated mice of the same age.
Xu’s lab is now testing drugs that target p21high cells in hopes of finding one that would work in humans. Leveraging immunotherapy technology to target these cells could be another option, Xu said.
The team also plans to test whether eliminating p21high cells could prevent or alleviate diabetes or Alzheimer’s disease.
Challenges and Criticisms
The research provides “important evidence that targeting senescence and the molecular components of that pathway might provide some benefit in the long term,” Vaughan said.
But killing senescent cells could come with downsides.
“Senescence protects us from hyperproliferative responses,” potentially blocking cells from becoming malignant, Vaughan said. “There’s this effect on aging that is desirable, but at the same time, you may enhance your risk of cancer or malignancy or excessive proliferation in some cells.”
And of course, we don’t necessarily need drugs to prolong healthy life, Vaughan pointed out.
For many people, a long healthy life is already within reach. Humans live longer on average than they used to, and simple lifestyle choices — nourishing your body well, staying active, and maintaining a healthy weight — can increase one’s chances of good health.
The most consistently demonstrated intervention for extending lifespan “in almost every animal species is caloric restriction,” Vaughan said. (Xu’s team is also investigating whether fasting and exercise can lead to a decrease in p21high cells.)
As for brain health, Vaughan and colleagues at Northwestern are studying “super agers,” people who are cognitively intact into their 90s.
“The one single thing that they found that contributes to that process, and contributes to that success, is really a social network and human bonds and interaction,” Vaughan said.
 
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