"Demography is destiny" is an old cliche often used by armchair economists and social scientists. Not all cliches are completely wrong though. And while demography is not always destiny, the age composition of a country's population has a major impact on its prospects. Countries with predominantly young and growing populations tend to have higher rates of economic growth, increasing property values and smaller government debts. Conversely, countries with large proportion of the elderly tend to have stagnant economies, falling property values and massive debts - to say nothing of the decline in toy sales. Unless demographic trends are reversed, such aging countries face bleak future.
What does this have to do with aging of the human body? Well, plenty, if you view the body as a population of cells that in some respects resembles human society. Notably, the body has its own "elderly" called senescent cells. Most animal and human cells have an equivalent of an internal clock allowing them to divide only a limited number of times. (This limit is called the Hayflick limit after the scientist who discoverer it. See our article on the cellular clock for details). Once a cell reaches the Hayflick limit it not only ceases to divide but also undergoes profound changes in its physiology and appearance, entering a state called senescense. When a cell enters senescense its metabolic activity declines, it increase in size and accumulates lipofuscin, the pigment responsible for age spots.
As we age, the number of young cells capable of dividing decreases while the number of senescent cells goes up, leading to the stagnation and decline of the "system as a whole." Senescent cells take up space and resources yet contribute little to the productive function of the body's organs and tissues. Furthermore, senescent cells may also be actively contributing to the aging process by producing molecules that promote inflammation. (Age-related increase in inflammation is an important mechanism of aging). In particular, researchers found than senescent cells produce abnormally high amounts of pro-inflammatory cytokines (hormones-like signaling molecules) interleukine-6 and interleukine-8.
Until recently, senescent cells received only modest attention from anti-aging researchers because they were thought to be more of a nuisance byproduct than an active contributor to the aging process. That changed after the breakthrough study by Dr Darren Baker and colleagues from Mayo Clinic published in the journal Nature in November of 2011. The Mayo Clinic researchers used a sophisticated genetic engineering technique to eliminate senescent cells from the tissues of laboratory animals (mice) without affecting normal cells. The mice thus treated turned out to be resistant to many common age-related deficits and ailments. In particular, the animals without senescent cells maintained high physical endurance well into old age, avoided wastage of muscle and subcutaneous fat, and didn't develop cataracts. The "revitalizing" effect of senescent cells elimination did not extend the life of the mice in the Mayo Clinic study. However, in order to speed up the experiment, Dr Baker et al used a special fast-aging strain of mice that tend to die of heart attacks at an early age regardless of the health of their tissues. The researchers plan to conduct a similar study on ordinary mice to see if their lifespan is extended -- but that will take at least three years.
Eliminating senescent cells in humans
The aforementioned Mayo Clinic study may be the first step towards developing a rejuvenating human treatment based on clearing senescent cells from body tissues. However, it is likely to be a long road. First, the results of the Mayo Clinic team need to be independently confirmed by other research teams in mice and perhaps other animals. Next, the genetic engineering technique the Mayo team used to clear the senescent cells in mice cannot be used in humans -- it is based on inserting a designer gene into mouse cells at the embryonic stage. Therefore, a human-friendly way to safely eliminate senescent cells from the body needs to be found. In principle, a human gene therapy targeted to a specific easily accessible tissue, such as skin, could be developed but this is likely to take at least a decade. A designer drug to do the trick may also be feasible - but again it would likely take many years to develop.
If the existing senescent cells in the humans body cannot be easily eliminated just yet, what about preventing any more of the normal cells from becoming senescent? Wouldn't this reduce further accumulation of senescent cells and slow down aging? Well, yes and no. Let me explain.
The molecular mechanism that triggers the state of senescence has to do with telomeres, the protective pieces of DNA located at the ends of chromosomes. After each cell division, telomeres become shorter as a consequence of the particular mechanics of DNA-replicating apparatus in animal cells. Shortening of a telomere below a certain limit makes the cell unable to divide further and also triggers a cascade of changes leading to the state of senescence. Therefore, one should be able to prevent senescence and preserve cells' ability to divide by preventing or reversing the shortening of telomeres. Luckily (or not), each cell is capable of producing a special telomere-lengthening enzyme called telomerase. In typical adult cells, telomerase is suppressed and thus does not interfere with their eventual senescence. Conversely, in stem cells (a very small minority of cells in an adult organism) telomerase is usually active and maintains long telomeres, which allows stem cells to keep dividing.
It is tempting to try to prevent or reverse the transition of normal adult cells to the state of senescence (by activating telomerase, for example). Unfortunately, experimental attempts to do so have produced mixed results so far. In one study, inserting a functional telomerase gene into fibroblasts (connective tissue cells common in the skin) made them divide in tissue culture (i.e. in the test tube) far beyond the Hayflick limit. In another study, researchers manipulated mouse genes in such a way as to block their ability to enter senescence (specifically, they knocked out the gene p16 required for the transition). Such p16-deficient mice had more physiologically youthful tissues that retained their regenerative capacity throughout life. However, p16-deficient mice had a shorter lifespan due to dramatically increased incidence of cancer.
It has been theorized that senescence is a natural mechanism whose role is to provide some degree of cancer protection. Indeed, most cells that begin dividing uncontrollably probably become senescent before becoming cancerous. However, the situation is far from clear cut. The accumulation of senescent cells at advanced age actually correlates with exponentially increasing risk of cancer. Furthermore, senescence is associated with inflammation and chromosomal instability, both of which are factors known to contribute to cancer.
Some experts believe that senescence has a dual role in cancer: it tends to protect from cancer early in life but, conversely, increases cancer risk in the older age. If that is true, then periodicaly eliminating all (or at least most) senescent cells from the body (like in the Mayo Clinic study) would likely be the best strategy. Unfortunately, this option is not yet practically possible in humans. On the other hand, preventing or reversing cell senescence (e.g. by telomerase activation) might also have a net benefit (in terms of both cancer risk and general rejuvenation) if used prudently and initiated relatively late in life.
There may be drug-like substances capable of activating telomerase and thus preventing or reversing cellular senescence. One such putative telomerase activator is TA-65, an agent originally isolated from astragalus plant by Geron corporation and currently being commercialized and distributed by TA Sciences. There is intriguing evidence indicating that TA-65 may indeed moderately activate telomerase. However, comprehensive studies are needed to determine its long-term risks and benefits in humans. It may turn out that mild-to-moderate activation of telomerase with TA-65 or similar drugs has acceptably low risk in older people. According to TA Sciences, orally administered TA-65 has so far demonstrated good safety and efficacy in humans. However, considering the link between telomerase activation and cancer demonstrated in animal studies, comprehensive independent studies of TA-65 are needed before it can be seriously considered as an anti-aging agent suitable for human use.
Bottom line
It appears that senescent cells play an active role in the aging process and eliminating them or reducing their accumulation in tissues may have rejuvenating effect. Unfortunately, at present there is no proven method to do this safely and effectively in humans. Until such method is available, your best bet is to slow down the accumulation of senescent cells in your body by reducing the rate of telomere shortening. The ways to do that are discussed in our article on the cellular clock.
