The Cell's Lifespan Timer: Can We Really Live Longer by Extending Telomeres?

This document was translated by Jules. Read the original Korean post here.

Can Cells Live Forever? The Belief That Dominated a Century

In the early 20th century, the scientific community was gripped by a single, powerful belief: “Cells are inherently immortal.” While the concept of senescent cells existed, it wasn’t accepted as dogma. This was all due to the unwavering faith in “cellular immortality.” At the heart of this belief were the research papers published by Nobel laureate Alexis Carrel and various other researchers. In 1912, Carrel announced that he had successfully cultured a piece of a chicken heart for an astonishing 34 years. This story of the immortal chicken heart spread worldwide, and with various labs announcing that cell lines extracted from cancer cells could divide indefinitely, it naturally gave rise to the powerful proposition that “cells can live forever, and aging and death are not the fate of the cell itself, but merely problems of the surrounding environment or culture techniques.”

Cell line vs. Cell strain: At the time, the terms Cell line and Cell strain were strictly distinguished. A Cell line typically referred to cells derived from cancer that could divide continuously and form malignant tumors upon inoculation, while a Cell strain referred to normal cells with a finite division limit.¹ Of course, in modern times, this distinction has become very blurred, and most cultured cells are simply referred to as cell lines.

However, a young scientist named Leonard Hayflick dared to question this established theory. In the early 1960s, while culturing various human-derived cells, he encountered a phenomenon completely different from Carrel’s claims. No matter how perfect the environment or how meticulously he cultured them, the cells would invariably stop dividing and die after about 50 divisions. It wasn’t just him; too many researchers were failing to replicate the “long-lasting cell lines” reported by others. In particular, no one could culture Carrel’s immortal chicken heart muscle cells for more than a year. What in the world was going on? With the prevailing notion that “cellular aging and death are problems of the environment or culture techniques,” Hayflick might have even thought he was doing something wrong. But science is about presenting well-founded evidence. He continued his persistent observations.

Was Carrel’s ‘Immortal Cell’ a Fraud? It was later revealed that Carrel’s experiment had a fatal flaw. Every time Carrel supplied nutrients to the cells, he used ‘chick embryo extract,’ which likely contained embryonic stem cells. In other words, wasn’t he just discarding dying cells and constantly supplying new, young ones? It might not have been a single chicken’s heart muscle maintained over time, but a chimera of many chickens.¹

A picture of `Leonard Hayflick` taken in 1975. Born in 1928, he published his paper in 1961 at the age of 33.
Source: Wikipedia https://commons.wikimedia.org/w/index.php?curid=154793519

In 1961, Leonard Hayflick, along with his colleague Paul Moorhead, announced this discovery to the world.² The small pebble they tossed shattered the great myth that had pervaded the scientific community. They revealed the incredible fact that there is always a limit to the number of times a cell can divide. This phenomenon, where the division cycle lengthens, waste products accumulate, dead cells increase, and the cell size gradually grows until division ceases, was named the ‘Hayflick Limit’ in his honor. This event taught another great lesson: “Just because someone is a Nobel laureate doesn’t mean they are always right.” Let’s remember that. There’s a whole bunch of Nobel prize winners who’ve said wrong things. Relying on authority can lead to big trouble.

The paper published by Paul Moorhead and Leonard Hayflick has been cited 11,640 times as of 2025, and a follow-up paper he authored alone in 1965 has been cited 8,430 times. How thrilling must it be to publish a paper that overturns common sense and gain recognition for it!

So… Aren’t Telomeres the Reason for the Hayflick Limit?

Structure of a Telomere

The structure of a telomere, which protects the end of a chromosome. This structure shortens slightly with each cell division.
Source: [Christina Loukopoulou et al., 2024, Cancers](https://www.mdpi.com/2072-6694/16/19/3370)

The existence of telomeres, now common knowledge, was actually known even before the Hayflick Limit. In 1938 and 1939, Müller and McClintock, studying fruit flies, discovered that the ends of chromosomes had a peculiar structure, which they named telomeres. However, they only knew it had a strange structure; they didn’t know it shortened. The realization that telomeres shorten came in 1967 when Reiji Okazaki and Tsuneko Okazaki discovered what is now known as the Okazaki fragment. At the time, it was naively assumed that DNA replication was a continuous process, but the Okazakis revealed this was not the case. They found that DNA replication not only has a direction but also involves the creation of short fragments that are later joined (ligated).³

The experimental techniques used to prove the existence of Okazaki fragments are truly astounding. Using radioactive labeling, DNA-degrading enzymes, and sedimentation techniques—technologies from an era without sequencing—they produced results that no one could refute. Isn’t that what a true scientist is?

The first person to link telomeres and the Hayflick limit was a Russian scholar named Alexey Matveyevich Olovnikov. In 1971, based on the understanding at the time, he proposed that telomeres would shorten and believed this was related to the Hayflick limit.⁴ Although the original paper was written in Russian and is not currently available online, an English version was published in 1973.⁵

The shortening of telomeres is due to a fundamental limitation of DNA replication known as the ‘End-replication problem.’ The enzyme that replicates DNA (DNA polymerase) moves along one of the two strands of the DNA railway, creating a new strand. To start, a small piece called a primer must first attach. The problem is that after replication is complete, this primer is removed, leaving a gap. In the middle of a chromosome, other enzymes can fill this gap, but at the very end of the chromosome, there is no way to fill this empty space. Surprisingly, the DNA replication process is this imperfect. Consequently, with each division, the cell loses a little bit of genetic information from the chromosome ends, and this is the cause of telomere shortening.

Telomeres are shortening, so why is that a problem?

The idea that telomere shortening is directly linked to cellular aging is actually quite strange. Telomeres shorten, yes, but they don’t contain crucial genetic information. It’s like using a pencil: the eraser on top wearing down doesn’t make the pencil itself unusable. Whether the telomere shortens or not, the genetic information containing the protein blueprint is safe. Yet, there’s a system that simply stops the cell from dividing. The reason for its existence is not important; the system is just there. Fine. So how does the cell know that its telomeres have shortened?

It’s easy to think that every system in a cell must have a reason for its existence. However, science is not a discipline that uncovers such reasons for being. Science is about figuring out what phenomena exist and how they work. The moment you start thinking about reasons for being, you fall into the teleological fallacy. Just as natural phenomena have no intent or purpose, biological systems do not have intent or purpose either. They only have their function.

Protein character looking at a broken DNA

A protein complex named ‘Shelterin’ plays a key role here. Shelterin normally binds tightly to telomere DNA, acting as a protector that ‘disguises’ the end of the DNA so it doesn’t look like a break. It prevents the cell's DNA damage surveillance system from mistaking the chromosome end for a real damage site and launching unnecessary repair operations. However, when telomeres shorten below a critical point, the Shelterin complex can no longer bind stably. The unprotected, naked chromosome end is exposed and finally recognized as ‘severe damage’ by the cell's DNA damage surveillance system (ATM, ATR, etc.). This signal activates tumor suppressor proteins like p53, which halt cell division and push the cell into a state of ‘cellular senescence’.

Cells don’t have eyes. Sometimes, DNA gets damaged and breaks. The middle part of such a break and the end of another chromosome are actually indistinguishable. The crucial element that allows the cell to tell them apart is a protein like Shelterin.

The concise and powerful formula, ‘The cause of aging is telomere shortening,’ was born.

The Dream of Eternal Life, or the Nightmare of Cancer

This simple formula immediately led to a single question:

“If we age because telomeres shorten, can we prevent aging by maintaining or extending telomere length?”

The Opposite Case: The Fate of Mice with Shortened Telomeres Scientists directly confirmed the effects of telomere shortening by creating ’telomerase knockout organisms,’ in which the gene for telomerase was artificially removed. The results showed a reduced lifespan, slower wound healing, and ‘premature aging’ phenomena like bone marrow failure. This is powerful evidence that telomere length is a direct cause of aging and lifespan.⁶

This bold idea stimulated countless scientists but also cast a giant shadow: ‘Cancer.’ One of the hallmarks of cancer cells is that they ‘don’t die,’ meaning they are immortal. Scientists discovered that cancer cells reactivate an enzyme called Telomerase to continuously repair shortening telomeres, thereby overcoming the Hayflick limit and proliferating indefinitely. There was a fear that if we artificially extended telomeres, we might end up spreading cancer throughout the body in our attempt to stop aging.

Two Survival Tactics of Cancer Cells: The Precise ‘3D Printer’ vs. The Desperate ‘Robbing Peter to Pay Paul’

Of course, not all cancer cells use only the telomerase method. About 10-15% of cancer cells use a more bizarre and desperate method called ‘Alternative Lengthening of Telomeres (ALT)’.

Telomerase Method: Telomerase is like an ultra-precise 3D printer with its own blueprint (RNA template). This printer flawlessly prints base sequence bricks like TTAGGG and stacks them neatly at the end of the chromosome. Our germ cells also use this method.
ALT Method: In contrast, ALT is pure copy-pasting. It’s based on a DNA repair mechanism called homologous recombination, used by organisms like us that have two copies of each chromosome. It involves copying and pasting from the other chromosome. Since telomeres have the same structure at the end of every chromosome, there’s plenty to copy from.

But Trying is the Fun of Science. Let’s Extend Telomeres!

Mad scientist character manipulating cells

Science is advanced by mad scientists!

In the late 1990s, scientists conducted an experiment to activate telomerase in normal cells that had reached the Hayflick limit. Through genetic manipulation, they induced the expression of hTRT in cultured cells, and the results were astounding. The cells that had stopped dividing and were aging began to divide vigorously again, managing about 20 more divisions than the original cells!⁷ This experiment became the definitive proof that telomere shortening is a direct cause of cellular aging.

At the same time, scientists breathed a sigh of relief. These lifespan-extended cells did not show malignant transformation, another characteristic of cancer cells. They had only gained the ability to divide a bit more; they didn’t grow uncontrollably like cancer cells. When cancer-causing genes (like Ras) were introduced, these ’lifespan-extended cells’ immediately stopped dividing and entered senescence or underwent apoptosis. In other words, the cancer suppression systems like p53 were still functioning normally.

Through this experiment, the scientific community realized an important fact: Immortality is just one of many steps toward cancer, not cancer itself. To become true cancer, a cell must not only gain immortality but also completely dismantle our body’s sophisticated cancer suppression systems. Nevertheless, for a while, telomere manipulation was considered a dangerous technology that could potentially cause cancer.

Overturning Common Sense: ‘Long-Telomere’ Mice Live Healthier, Longer Lives

The Maria Blasco research team took on the challenge of extending telomeres at the whole-animal level. Instead of directly manipulating genes, they utilized the natural phenomenon of telomere lengthening during the culture of embryonic stem cells. By controlling the culture time, they created embryonic stem cells with hyper-long telomeres and used these cells to clone mice. Mice were born with all their cells having much longer telomeres than normal.⁸

The results were astonishing. These mice had an average lifespan 13% longer than normal mice. And they didn’t just live longer. They were leaner, had lower cholesterol levels, and showed improved insulin resistance, enjoying a much healthier old age.

The most shocking part was the ‘cancer incidence rate.’ Shattering everyone’s expectation that telomere extension would cause cancer, these mice actually had a lower rate of cancer. The research team speculated that the long telomeres made the chromosomes themselves more stable, reducing DNA damage and mutations. This study proved the formula ’telomere extension equals lifespan extension and health improvement’ to the world.

Extending Lifespan with Gene Therapy Too In fact, in 2012, the Blasco team had already attempted ‘gene therapy’ by delivering the telomerase-making gene into one- and two-year-old mice using a virus. The result was equally successful. The lifespan of one-year-old mice was extended by 24%, and two-year-old mice by 13%. This was an important study showing that telomere therapy could be effective even in already aged individuals.⁹

These amazing results clearly show that telomeres play a key role in mammalian aging. But in this vast and diverse sea of life, is everyone really facing this telomere-induced limit?

The Hayflick Limit and telomere shortening have become a powerful curse that makes us mistakenly think telomeres are everything in aging!

Life’s Diverse Aging Strategies

Unfortunately, the story of life is not that simple. Organisms have evolved in their own unique ways. From now on, let’s look at the stories of other organisms that cannot be explained by telomeres alone.

Friends who don't care about telomeres

The Aging of Insects Without a Telomere Clock

The world of insects is very different from our common understanding. Even within insects, there are vastly different telomere structures. For example, flies and mosquitoes have structures that look like telomeres, but they are not typical telomeres. In flies, a bizarre structure called a retrotransposon, which can move between chromosomes, serves the role of their telomeres, while mosquitoes maintain length through satellite repeats-based recombination. Moreover, creatures like flies and mosquitoes don’t even have telomerase. Despite this, most insect cells maintain a constant telomere length throughout their lives.

In other words, the time bomb of telomere shortening doesn’t exist in the first place. But insects still age and die. Their aging is understood not to be due to telomeres, but to the inevitable accumulation of ‘reactive oxygen species’ leading to damage to proteins and DNA, and ‘waste products’ from metabolic processes. In fact, this kind of damage also occurs in mammalian cells. This means mammalian aging is a double whammy of 'telomere shortening' and 'other cellular damage'.

The Secret of Plants That Endure for Millennia: The Wisdom of the Meristem

So what about trees that live for thousands of years? Unlike animals, plants are fixed in one place and have to endure the sun’s UV rays and various stresses with their whole body. How do they seem to overcome aging?

The meristem at the tip of a plant root. In the center is the slow-dividing 'Quiescent centre,' and the surrounding cells divide to form tissues.
Source: 10.3390/antiox12071330

The key lies in a marvelous stem cell system called the ‘meristem.’ Of course, we have stem cells too, but while animal stem cells accumulate aging damage as they divide, the plant meristem shows a vitality that is almost immortal.

The secret lies in multiple layers of sophisticated protection. At the core of the meristem is a group of extremely slow-dividing cells called the ‘Quiescent Center.’ These are a kind of ‘stem cell master copy,’ which minimizes their activity to reduce the risk of mutations that can occur during DNA replication. They are a highly efficient backup system, dividing only when surrounding tissues are damaged to supply new stem cells. Furthermore, plant stem cells have a much more robust and sensitive DNA damage repair system and control mechanisms that perfectly maintain their epigenetic state, giving them an outstanding ability to block the fundamental causes of aging at the source.¹⁰

Humans have quiescent cells too! The egg cell (ovum) is a prime example of a quiescent cell. It pauses its division midway and completes it only during each menstrual cycle. Thanks to this, it is more resistant to division-related damage compared to sperm. But then why does menstruation have to be so painful…

Yeast is Tough: “I Get Old, But My Child is Always New”

Yeast is a very peculiar organism. It’s a single-celled eukaryotic organism. Being single-celled means that its division is its reproduction. If this yeast had a Hayflick limit, how could it possibly persist through generations?

A yeast cell in the process of dividing. The aged Mother cell is giving birth to a young and healthy Daughter cell.
Source: By Mogana Das Murtey and Patchamuthu Ramasamy - https://www.intechopen.com/chapters/49652, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=52254246

When yeast divides, the mother cell takes on all the cellular ‘garbage’—damaged protein aggregates, dysfunctional mitochondria, and specific aging-related factors. It then passes on only clean and healthy cytoplasm to the newborn daughter cell. The generation continues to maintain its youth, while the individual that created it ages by taking on all the damage. This is an amazing strategy called ‘Asymmetric Aging.’¹¹ Through this, the risk of aging from the general environment is borne only by the mother. Crucially, yeast always has active telomerase, so its telomere length remains constant!

Conclusion: Aging is a Giant Puzzle, and Telomeres are Just the Beginning

The story of telomeres is fascinating enough to captivate us. A clever timer that counts cell divisions, and the sight of a mouse’s lifespan being healthily extended when its length is increased, makes it seem as if we have unraveled the first thread of the great destiny of aging. Looking at it from every angle, everyone links telomeres and aging, to the point where it feels like telomeres are the absolute cause of aging.

But the world of life is far more colorful and complex than we think. Insects that undergo their own aging process without a telomere clock, plants that endure for thousands of years with a nearly immortal stem cell system, and the wisdom of yeast that willingly grows old for the sake of the next generation clearly show that the formula ’telomere shortening = aging’ is not an absolute law that applies to all living things.

Ultimately, for us mammals, telomeres are just one factor, not the sole determinant of everything. Therefore, while the technology to extend telomeres is undoubtedly a key piece of aging research, it is not the master key that will unlock the door to eternal life.

Aging is a giant puzzle woven from countless pieces, including damage from reactive oxygen species, epigenetic changes, and the collapse of protein homeostasis. Telomeres are just one conspicuous piece of that puzzle. Starting with this piece, we have only just begun the great journey to understand the full picture of aging.