The reality on the ground is much more complex than this simple view of a cell division countdown. Some cells don’t divide and last you a lifetime, such as many of those in the central nervous system. Other cells, such as stem cell populations, have their telomeres repeatedly extended by the enzyme telomerase. Different cells in different parts of the body have very different life spans, and the complex array of processes that determine those life spans is highly variable, reacting to the environment and to each other.
None of this really has much direct bearing on the life span of an organism, however. You can’t just wave a wand that would extend the life of all cells, and expect to see a similar extension of life in the organism – whether that happens or not depends on the intricate details of how cells relate to organs and systems. The life span of cells is all the way down there in the depths of the machine, details internal to low-level components that are decoupled from how the machine behaves in aggregate. There is no particular reason for cell life spans to have anything to do with how long the machine as a whole can last. Some of our tissues are designed to cycle through and replace all of their cells very rapidly, in a matter of days. Other cells are never replaced and live as long as we do.
Cell behavior is subordinate to the needs of the organ or system that they are a part of. The cells of a given type evolved to have their present behavior and typical life spans because, when acting as a system in conjunction with other cell types, they produce a working organ or system that provides some evolutionary advantage. If that can be done with lots of cell turnover and short cell life spans, it will be. If it can be done with little cell turnover and long cell life spans, it will be also – but either path can produce a long-lived and reliably functional organ. This point is one that a recent article comes to eventually, after a tour of the Hayflick limit and telomere biology: It is true that as we get older our telomeres shorten, but only for certain cells and only during certain times. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear. Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; the Colosseum degraded because the Roman Empire fell. Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.
The processes that cause degenerative aging occur at the level of cells and specific protein machinery within cells, harming their ability to perform as they should. Old, damaged cells produce more old, damaged cells when they divide. Old, damaged stem cells simply fail to keep up with their tasks of tissue maintenance. Long-lived cells become progressively more damaged and incapable, or die back, either of which causes very visible issues when it happens in the nervous system and brain.
Aging is simply a matter of damage. But how that damage translates into system failure is not a straightforward matter of cells living longer or cells dying sooner – except when it is for some long-lived cell types. Every tissue fails through the same general processes, but those processes produce a very wide range of failure modes, depending on the character of the tissue and the cells that make it up. Go beyond the comparative simplicity of the root causes of aging, and everything becomes progressively ever more complex as you move towards describing the highly varied biology of fatal age-related diseases. This is why intervening in the root causes is absolutely the best and most cost-effective strategy, the only one likely to produce meaningful progress towards human rejuvenation in our lifetimes.
Plateau Effect of Aging
In rich countries, more than 80% of the population today will survive past the age of 70. About 150 years ago, only 20% did. In all this while, though, only one person lived beyond the age of 120. This has led experts to believe that there may be a limit to how long humans can live.
Animals display an astounding variety of maximum lifespan ranging from mayflies and gastrotrichs, which live for 2 to 3 days, to giant tortoises and bowhead whales, which can live to 200 years. The record for the longest living animal belongs to the quahog clam, which can live for more than 400 years.
If we look beyond the animal kingdom, among plants the giant sequoia lives past 3000 years, and bristlecone pines reach 5000 years. The record for the longest living plant belongs to the Mediterranean tapeweed, which has been found in a flourishing colony estimated at 100,000 years old.
The natural laws of physics may dictate that most things must die. But that does not mean we cannot use nature’s templates to extend healthy human lifespan beyond 120 years.
Putting a Lid on the Can
Gerontologist Leonard Hayflick at the University of California thinks that humans have a definite expiry date. In 1961, he showed that human skin cells grown under laboratory conditions tend to divide approximately 50 times before becoming senescent, which means no longer able to divide. This phenomenon that any cell can multiply only a limited number of times is called the Hayflick limit.
Since then, Hayflick and others have successfully documented the Hayflick limits of cells from animals with varied life spans, including the long-lived Galapagos tortoise (200 years) and the relatively short-lived laboratory mouse (3 years). The cells of a Galapagos tortoise divide approximately 110 times before senescing, whereas mice cells become senescent within 15 divisions.
The Hayflick limit gained more support when Elizabeth Blackburn and colleagues discovered the ticking clock of the cell in the form of telomeres. Telomeres are repetitive DNA sequence at the end of chromosomes which protects the chromosomes from degrading. With every cell division, it seemed these telomeres get shorter. The result of each shortening was that these cells were more likely to become senescent.
Other scientists used census data and complex modelling methods to come to the same conclusion: that maximum human lifespan may be around 120 years.But no one has yet determined whether we can change the human Hayflick limit to become more like long-lived organisms such as the bowhead whales or the giant tortoise.
What gives more hope is that no one has actually proved that the Hayflick limit actually limits the lifespan of an organism. Correlation is not causation. For instance, despite having a very small Hayflick limit, mouse cells typically divide indefinitely when grown in standard laboratory conditions. They behave as if they have no Hayflick limit at all when grown in the concentration of oxygen that they experience in the living animal (3-5% versus 20%). They make enough telomerase, an enzyme that replaces degraded telomeres with new ones. So it might be that currently the Hayflick “limit” is more the Hayflick “clock”, giving readout of the age of the cell rather than driving the cell to death.
The Trouble with Limits
Happy last few days? It doesn’t have to end this way. ptimat
The Hayflick limit may represent an organism’s maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit’s ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person’s cells should divide far fewer times than a 20-year-old’s cells.
But this experiment fails time after time. The 60-year-old’s skin cells still divide approximately 50 times – just as many as the young person’s cells. But what about the telomeres: aren’t they the inbuilt biological clock? Well, it’s complicated.
When cells are grown in a lab their telomeres do indeed shorten with every cell division and can be used to find the cell’s “expiry date.” Unfortunately, this does not seem to relate to actual health of the cells.
It is true that as we get older our telomeres shorten, but only for certain cells and only during certain times. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.
Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; the Colosseum degraded because the Roman Empire fell.
Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.
To Infinity and Beyond
If we could maintain our body’s ability to repair and regenerate itself, could we substantially increase our lifespans? This question is, unfortunately, vastly under-researched for us to be able to answer confidently. Most institutes on aging promote research that delays onset of the diseases of aging and not research that targets human life extension.
Those that look at extension study how diets like calorie restriction affect human health or the health impacts of molecules like resveratrol derived from red wine. Other research tries to understand the mechanisms underlying the beneficial effects of certain diets and foods with hopes of synthesizing drugs that do the same. The tacit understanding in the field of gerontology seems to be that, if we can keep a person healthy longer, we may be able to modestly improve lifespan.
Living long and having good health are not mutually exclusive. On the contrary, you cannot have a long life without good health. Currently most aging research is concentrated on improving “health,” not lifespan. If we are going to live substantially longer, we need to engineer our way out of the current 120-year-barrier.
Because cells are the fundamental building blocks of our bodies, it is logical to assume that cellular changes contribute to the aging process. In this essay I review the methods used to study cellular aging in vitro, in particular replicative senescence, and debate whether these findings could be related to organismal aging.
Limits on Cell Life Span Have Little To Do With Limits on Organism Life Span