The promises and perils of research on aging: Come grow old along with me

What does it mean to age? Is it some random accumulation of bodily damage that can’t be helped? Or does it involve an organized process that biologists can study and reverse? If you are thinking that the latter raises all sorts of social questions, you are right, but hold on while I tell you one story about the biology of aging. 

Animal cells divide in a petri dish if fed the right broth of nutrients. Their numbers increase exponentially until they touch each other and then they stop dividing. Scrape them up; dilute them in a dish with fresh nutrient broth, and they grow again. This is a passage of cells that is the endless task of graduate students preparing cells for experiments.  

In 1961, Leonard Hayflick and colleagues noted that after 40 or 60 passages, their cells stopped dividing, even at low density. This failure to grow became known as the Hayflick Limit. The cells didn’t die; they just looked stressed and unhealthy. Dr. Hayflick suggested that this arrest of division was the counterpart of human aging and called it senescence. Many biologists attacked him for over- reaching. He was right in the end, but it took five decades to prove it. 

We have learned that cells become senescent when stressed.  Stresses come in many forms: a virus, starvation, radiation or damage to the cell’s DNA, especially those bits at the ends of chromosomes called telomeres. Many forms of stress stop cell division, probably as a protection against cancer. Senescence is an orderly process, step two follows step one; it’s not like your car rusting and the water pump breaking and the muffler falling off — things that happen in any order. 

After blocking cell division, the second step for a senescent cell is to hold off death. Animal cells have suicide plans built into their genes and often die when they receive a biochemical signal. The process is called apoptosis and is essential for various developmental and immunological processes. In senescent cells, the suicide signals are countermanded and they live on as undead, or zombie cells, as some have described them.  

With time, lots of these zombie cells accumulate in skin, liver, kidneys, joints and other tissues. They are not benign. The third step carried out by senescent cells in the tissues is to secrete a whole catalogue of proteins, including cytokines and interleukins that stimulate the immune system. That activation of the immune system causes continuous inflammation, which damages healthy cells in tissues and is a cause of aging.

Allow me a metaphor. Many of us have been to family gatherings where a vocal relative sits on the couch and spews complaints and insults, ruining everyone’s day. That’s what senescent cells do in the tissues of aging people (or more practically for experimental purposes) in mice. 

What is the therapeutic equivalent of silencing the obnoxious guest at Thanksgiving? One idea is to turn the mechanism of cell death back on, unleashing enzymes that chop up a senescent cell’s DNA. That would remove them from the tissue, which could then repair itself. 

Geneticists have bred mice in which the mechanisms that protect senescent cells from suicide can be turned off.  One study employed a special breed of mouse that ages prematurely. (There are equivalent human diseases like progeria.) 

When senescent cells were killed in the tissues, the aged and sparse hair of the mice became thicker and regained its vigor. Other aging tissues also recovered. Removing senescent cells allows repair to occur, or at least that is the interpretation. Other experiments of this type led to what appeared to be (I am a little skeptical) a 25-percent increase in mouse life span.  

Mice are imperfect genetic models for human diseases and researchers are worried that the results derived from mice will not extend to humans, which often happens. The research is progressing very fast. We’ll see soon if a 50-year-old observation in basic research will now bring therapeutic blessings. 

The drugs that kill senescent cells are called senolytics and a number are now in clinical trials (search Clinicaltrials.gov). The field has attracted enormous attention and lots of money, a lot of it private (see The Buck Institute, for example). The potential of eliminating senescent cells is usually justified in terms of extending healthy life-span, not necessarily extending the years one lives. Delaying the onset of neurological diseases of aging would save a fortune of misery and expense.

Yet, since we live in an age of grandiosity, there are those who might use these developments to try living to 150. That would be an exercise in hubris with negative consequences that readers can surely imagine.

Richard Kessin, PhD is Professor of Pathology and Cell Biology Emeritus at Columbia University. He lives in Norfolk and can be reached at Richard.Kessin@gmail.com. Contact him for original papers on aging that he read in preparation for this column.