Can we ‘reboot’ the clock on aging?

There are three ways humans — probably all living things — die: injury, disease and due to the “zombie cells,” quipped a septuagenarian gerontologist kibitzer friend. Empirical studies show that over time, most of us might have been better able to dodge injury and disease because of safer and salubrious technology and sufficient wealth.

The “zombie cells,” however, remain finitely inevitable.

Take Ming for instance the oldest animal that survived for 507 years. Ming was an Ocean Quahog, a clam collected off the coast of Iceland in 2006. Ming’s age was based on its shell’s annual rings. It is a non-colonial animal, meaning unlike corals, it is not composed of “polyps” collectively stuck together, and it can live to over 4,000 years.

Among humans, the oldest officially recorded was a French woman named Jeanne Louise Calment born in 1875, who died in 1997. Calment survived for a staggering 122 years. This seems to defy a contemporary study conducted in The Netherlands suggesting that the maximum ceiling life span for females is 115.7 years and slightly lower for men at 114. Calment’s record skewed this finding by more than six years.

Today, “On average, people live longer, but the very oldest among us have not gotten older over the last thirty years. There is certainly some kind of a wall here,” according to Dr. J. Einmahl of Tilburg and Rotterdam’s Erasmus University. The rub is, although “the average life expectancy has increased; the maximum ceiling has not changed,” added Dr. Einmahl.

Can humans possibly live for 500 years like Ming? Can we breach the “wall?” Can we really “reboot” the clock on aging, reverse or slowdown or increase life span, evade, eschew or stave it off?,  quizzically quipped a geneticist kibitzer with a progeria-afflicted child.

Studies suggest that a human being’s maximum lifespan plateaus in the 90s and unlikely to ever increase beyond 115 years.

Zombie

“Zombie cells” are human cells that stop proliferating after being subjected to any predisposing and precipitating “interventions” or stress relative to their replicative bio-physiological or chemical capabilities, that experts suggest, or speculate, lead to aging.

Zombie cells are the senescent cells in medical jargon; “senescence” was discovered by microbiologists Drs. L. Hayflick and P. Moorehead, who coined the term in their 1961 oft-quoted pioneering study The Serial Cultivation of Human Diploid Strains. This started the categorizing of aging on a cellular level.

Senescent cells are cells that “secrete harmful proteins and chemicals, creating a sort of a “toxic soil” … that disrupts every bodily system and function,” according to Dr. N. LeBrasseur, a researcher at the Mayo Clinic Center for Regenerative Medicine and lead investigator in regenerative medicine.

It is like a robust secretory-killing machine pumping out fancy sounding chemicals like cytokines, chemokines, extracellular matrix proteases and others into the body systems, creating all kinds of havoc; compromising the health and function of neighboring cells and the surrounding tissue, according to Dr. LeBrasseur.

This process can sap the body’s ability to replete newer cells, heal from injury and ultimately leads to what we might loosely call “getting old or aging,” so we are told. In developmental psychology, aging is defined simply as the biological and psychological changes associated with chronological age.

However, we are also told that there is a distinction often made between changes that are due to normal biological processes, i.e., the distinctly senescent, and changes that are caused by age-related pathologies or “secondary aging.”

Secondary aging are changes akin to biological aging but are “accelerated” by disabilities caused by disease or any extrinsic factors, trauma, and lifestyle. It is often distinguished from primary aging or basically “senescence” that is governed by inborn and age-related processes. However, the delineation is not always precise, so we are told.

Could the senescent cells be the “wall” that Dr. Einmahl speculated about? A Filipino bugtong (riddle) comes to mind: Kung gusto mo akong mabuhay, bayaan mo akong patay. Kung gusto mo akong mamatay, bayaan mo akong buhay. Ano ako? (If you want me to live, let me be dead; if you want me to die, let me live. What am I?).” The answer is at the end of this piece.

Reverse

Bryan Johnson, 45, is a successful software entrepreneur who organized a team of 30 doctors and health experts to monitor his every bodily function. He apparently allowed these experts to “tinker” with his body, as a billionaire human guinea pig, quipped an evolutionary biologist kibitzer friend.

The team is led by 29-year-old regenerative medicine specialist, Dr. O. Zolman, committed to helping reverse the aging process in all of Johnson’s organs: “to have the brain, heart, lungs, liver, kidneys, tendons, teeth, skin, hair, bladder, penis and rectum of an 18-year-old.”

The team dubbed this the “Project Blueprint.” The plinth of the project is pivoted on “self- quantification” pioneered by Dr. L. Smarr, a Nobel laureate, astrophysicist turned computer scientist. Dr. Smarr started charting his bodily inputs and outputs a decade ago in minute details — from sleep to the state of his poop – formulating a true ecology of his quantified self.

This was the precursor of “self-tracking” first proposed by G. Wolf and K. Kelly, editors of Wired Magazines, in 2007. Self-quantifying is the ‘self-tracking’ of our own physiology, behaviors, genome, down to cellular activities.

The primary goal: to determine the harbingers of one’s current and/or future health conditions including every human microbiome, body system, molecule and cell.

Complexify

However, Johnson’s team integrated strict Project Blueprint program to include diet, exercise, endurance of dozens of medical procedures (some quite extreme and painful) then measured the results with additional biophysiological tests, whole body MRIs, ultrasounds, colonoscopies and skin acid peels, laser and sound therapy, among others.

The program can sound deranged and the methods might strike some as biotech-infused snake oil, wrote author-columnist A. Vance, in his 2023 Bloomberg article. “This is expected and fine,” was Johnson’s response to criticism.

Dr. O. Zolman, it might be worth noting, opened his own firm, 20one Consulting Ltd., in Cambridge, England in 2021. “My goal is to prove through biostatistics a reduction of aging of 25% across all 78 organs by 2030. It’s an extremely hard and crazy idea,” stated Dr. Zolman during an interview.

The program costing $1,000 includes lots of testing, monitoring, therapies and applications of expensive medical devices. Dr. Zolman does not charge if the patient does not see results, we are told again. There is the “rob,” quipped an actuarial analyst kibitzer friend.

Slowdown

Similarly Mayo Clinic, one of the world’s renowned purveyors of medical studies had been doing studies on aging not to reverse it but “to solve the puzzle of why the body’s healing abilities wane as a person grows older.” Mayo is shifting its therapeutic paradigm from treating disease to restoring health in their Center for Regenerative Medicine, in collaboration with the Robert and Arlene Kogod Center on Aging.

Unlike Project Blueprint, the aim of Mayo’s research is “not to increase life span (or reverse aging), but to increase health span — delaying the onset of disease and disability as long as possible in order to live a healthier, higher quality of life in the years a person does have.”

Mayo’s studies are probing ways to activate the body’s regenerative potential to slow the clock on chronic conditions that set in as we age, from cancer to diabetes to Alzheimer’s and a person’s risk of developing chronic disease, reported S. Buckles in her 2020 article, Turning Back The Clock On Aging.

As early as 2011, Mayo’s pioneering study already revealed that removing senescent or “zombie” cell could halt the aging process and restore tissue regeneration in an organism, which, looking back after more than half a century ago, was based on Drs. L. Hayflick and. P. Moorehead “zombie cells” study.

More contemporary studies are showing that clearing senescent cells – through genetic, pharmacological and other interventions — improves age-related diseases of the lung, bones, vasculature, brain, kidney, liver and other organs. Probably where Project Blueprint’s plinth was cast, quipped another biomedical-scientist kibitzer friend.

Regenerate

The research team at Mayo Center for Regenerative Medicine also claimed their study “shows that targeting senescent cells can markedly improve the health and function of an organism” and in part enhances tissue rejuvenation. Suggesting that, “if you get rid of senescent cells, you may be able to improve healing and tissue regeneration in older adults following injury,” according to Dr. N. LeBrasseur, the lead investigator.

The Center is interested in answering two key questions in the context of regenerative medicine: Could removing toxic senescent cells improve the body’s own regenerative potential in later life? Can senescent cell clearance be a kind of pre-treatment for emerging regenerative therapies, such as stem cells or stem cell-derived products?

Regenerative Medicine is a multidisciplinary field of therapeutic modalities that basically aim to augment, repair, replace or regenerate tissues and organs. The field involves three broad overlapping technology domains: cell therapy, gene therapy, and tissue engineering according to the Johns Hopkins’ academic program.

Is there currently a specific drug to clear the zombie cell in regenerative medicine? Amazon might have it, quipped a reductionist kibitzer friend; “branded” the senolytic drug, a.k.a., as the “activator life extension (!)” Not the Amazon forest of course, added this kibitzer.

Senolytic

Senolytics was developed at Mayo Clinic claiming to clear the bloodstream of senescent or “zombie” cells. Mayo study shows senolytic drugs can boost a key protein in the body that may protect older people against aspects of aging and a range of diseases; the result was demonstrated in mice and humans, wrote B. Nellis of the Mayo Clinic Public Affairs.

The study reveals that zombie cells basically contribute to multiple diseases and negative aspects of aging. This study also shows that the removal of senescent cells significantly boosts the production of a protective protein called a-klotho, added Nellis.

“The protein a-klotho is important to maintaining good health, as it tends to decrease with age, and especially decreases in multiple diseases, including Alzheimer’s, diabetes and kidney disease,” according to Dr. J. Kirkland, a Mayo Clinic internist and senior author of another Mayo study.

Animal studies have shown that decreasing a-klotho in mice shortens life span and increasing a-klotho in mice by inserting a gene that causes its production increases life span by 30%. It also shows that senolytics, administered orally, increase a-klotho in humans with idiopathic pulmonary fibrosis, a senescence-associated disease that leads to frailty, serious breathing difficulties and death. The National Institute of Health (NIH) supported this study, so we are told.

“Discovering ways to increase a-klotho in humans has been a major research goal, but that has been difficult because of its size and instability. Introducing it directly is problematic, as it would have to be administered into a vein instead of by mouth,” again according to Dr. Kirkland.

Moreover, and this is the rub, therapy to eliminate senescent cells has yet to be approved by the Food and Drug Administration (FDA), so we are told. This is in spite of the fact that, we not only understand why and how organs functions, but also how and why molecules react to specific interventions.

Another study in 2016 reveals, “Just by removing senescent cells, you could stimulate new tissue production,…” It jump-starts some of the tissue’s natural repair mechanisms,” stated Dr. J. Elisseeff, senior author and a biomedical engineer at Johns Hopkins University in Baltimore, Maryland. The study was done on mice.

Limit

Drs. L. Hayflick and P. Moorehead in pioneering categorizing aging on a cellular level in their 1961 study lead to the development of The Hayflick Limit concept in 1965, while Dr. Hayflick was at the Wistar Institute in Philadelphia, Pennsylvania almost 60 years ago.

‘The Hayflick Limit’ is a concept that helps to explain the mechanisms behind cellular aging. The concept states that a normal human cell can only replicate and divide forty to sixty times before it cannot divide anymore and will break down by programmed cell death or apoptosis. The “wall” that Dr. J. Einmahl speculated?

Yet in 2000, Dr. L. Hayflick presented in Nature that aging is an inexorable biophysical process that cannot be altered by eliminating senescent cells. “Efforts to interfere with the aging process have been going on since recorded human history… And we know of nothing—nothing— that has demonstrated to interfere with the aging.”

That was two decades ago, today, today another researcher reminds us that senolytic drugs will clear only senescent cells that are already present—they will not prevent the formation of such cells in the future, which means that senescence can continue to perform its original havoc- suppressing role in the body.

“If eliminating senescent cells in humans does improve age-related illnesses, researchers will aim to create broader anti-aging therapies,” according to Dr. N. David, a biotech scientist and co-founder of Unity Biotechnology in 2011.

Dr. J. Kirkland, another gerontologist at Mayo who took part in the 2011 study, bluntly admitted “I lose sleep at night because these things always look good in mice or rats, but when you get to people you hit a brick wall,” relating to a handful of small, proof-of-concept trials that pit senolytic drugs against a range of age-related ailments.

“No other anti-aging elixir has yet cleared that wall, and for a few good reasons. It is next to impossible to get funding for clinical trials that measure an increase in healthy lifespan. And even as a concept, aging is slippery,” added Dr. Kirkland.

The US Food and Drug Administration (FDA) has not (yet) labeled it (aging) a condition in need of treatment.

Natural

Scientists from various disciplines are currently frustrated by FDA stand on aging. However, there is one ‘natural-senolytic’ that can prevent senescent cell accumulation and, to some extent, eliminate senescent cells from the body: Exercise! Exercise (and healthy diets) could act as a natural therapy, studies reveal time and time again.

 “Exercise has profound effects on our cells and their capacity to repair different aspects of cell damage that are linked to aging and age-related diseases. For example, exercise improves the cells’ ability to repair DNA, manage oxidative stress, and turn on the garbage disposal and get rid of old damaged proteins,” according to Dr. Dr. LeBrasseur of Mayo.

“Exercise is regenerative medicine,” declared Dr. LeBrasseur. Moreover, annihilation of the ‘zombie’ cells by medications, diet, salubrious life style or a combination thereof cause or reverse the loss of regenerative abilities anchoring to aging.

Battery

Nevertheless, one self-declared-genius, cacophonously becoming infamous once haughtily professed his own theory of why exercise is bad for you. In the book “T Revealed,” M. Kranisch and M. Fisher of the Washington Post wrote on his “battery” theory of energy (exercise):

“After college, after T mostly gave up his personal athletic interests, he came to view time spent playing sports as time wasted. T believed the human body was like a battery, with a finite amount of energy, which exercise only depleted. So he didn’t work out. When he learned that John O’Donnell, one of his top casino executives, was training for an Ironman triathlon, he admonished him, “You are going to die young because of this.”

Anyway, the answer to the riddle is “Candle.” A good analogy for Mr. T’s “battery theory?” Or a good personification of Mr. T?, quipped a satirist-bioengineer kibitzer friend.

You be the judge.

NOTE: Mayo Clinic Staff forewarns us that healthy aging is a hot topic. Eating a variety of nutritious foods, practicing portion control and including physical activity in your daily routine can go a long way toward promoting healthy aging. If an interest in healthy aging leads you to consider anti-aging therapies such as restrictive diets, supplements or expensive treatments claiming to postpone or even reverse the aging process — be cautious. There is no quick fix when it comes to healthy aging. Often, anti-aging therapies do not live up to the claims.

Dr. Aggie Carson-Arenas is a Certified Clinical Psychology Specialist, a former associate professor and university research director. His latest book is, “You’re Okay, I Am Perfect (How Teens, Adolescents & Those In-Between Quest for Identity)” co-authored by her daughter Abbygale Williamson Arenas-de Leon. [email protected].