One reads a lot about the role of telomeres in aging, as well as other biomedical phenomena like stress and various diseases. But what exactly are telomeres? Why are they so important? What is the evidence they may be helpful for increasing healthy lifespan?
Telomeres were first discovered in the 1930s, when the ends of linear human chromosomes were found to have structures that prevented different chromosomes from attaching to each other. In 1973, Alexey Olovnikov observed that the ends of human chromosomes could not replicate completely (in the 5’ to 3’ direction), necessitating that chromosomal ends would shorten with each replication, eventually resulting in a critical point where DNA replication and cell division would permanently cease. This observation implied that cells contained an enzyme that could catalyze the lengthening of chromosomal ends. In 1984, Elizabeth Blackburn discovered the enzyme telomerase in the ciliate Tetrahymena, which has the ability to lengthen chromosomal ends by its reverse transcriptase activity, i.e., the ability to synthesize DNA from an RNA primer. In 2009 Blackburn, Carol Greider and Jack Szostak were jointly awarded the Noble Prize in Physiology or Medicine “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”
Several thousand studies have been published on telomeres and telomerase, which are now known to maintain genomic stability, prevent the inappropriate activation of DNA damage pathways, partially determine disease susceptibility/resistance and regulate cellular and organism-wide viability and aging. Telomerase expression also extends the lifespan and reverses senescence-associated pathologies in mice. Here I will briefly review telomere and telomerase function and the possibility of altering telomerase activity in humans to lessen the severity and incidence of age-related diseases and increase the human lifespan.
Telomeres are highly conserved throughout eukaryotic evolution, indicating a very ancient origin. In mammals they are a six-base repeat (TTAGGG) and in humans are 0.5 to 15 kilobases long. Telomeric ends typically shorten with each cell division/chromosomal replication, usually by 50-200 base pairs. After about fifty cell divisions, the shortened telomeres cause cells to lose their ability to divide and permanently senesce, an event called the Hayflick Limit.
Such non-dividing senescent cells adopt a characteristic senescent morphology (flat, enlarged cells), and show altered secretory profiles linked to many of the inflammation-related diseases of old age. The senescent morphology and inability to divide is reversed by telomerase expression and is accompanied by telomere elongation, demonstrating that telomerase activity can reverse age-associated cellular changes. In fact, human cells constitutively expressing telomerase will grow indefinitely in culture, exhibit no senescence-associated changes even after hundreds of cell divisions and are more resistant to the damaging effects of radiation and oxidants than are normal cells. In normal human cells telomerase is expressed in stem cells, cells that need to actively divide (like immune cells) and is barely, or not expressed at all in differentiated somatic (body) cells.
In humans telomere length and integrity plays a role in some diseases, disease susceptibility, aging and even in mediating the deleterious effects of long-term psychological stress. Several human genetic diseases are caused by alterations in telomerase function. For example, individuals with dyskeratosis congenita (DC), a disease caused by telomerase mutations, show bone marrow failure with anemia, premature aging, nail degeneration, testicular atrophy, abnormal skin pigmentation, an increased cancer incidence and significantly shortened lifespans. Many aspects of DC resemble normal aging, although at an accelerated rate. Individuals with DC are born with unusually short telomeres and not surprisingly, the expression of unmutated telomerase in DC cells corrects many of their molecular defects and lengthens their telomeres.
Normal cellular telomerase expression is insufficient to prevent telomere shortening with each cell division and hence, telomeres shorten with aging, eventually causing age-related changes. The process is complex, and different cell types and organs show different rates of telomere shortening, although overall telomere shorten most rapidly in growing cell populations. Interestingly, high telomere stability correlates with human longevity while caloric restriction (the only known intervention that increases the mammalian lifespan), reduces the rate of telomere shortening, although it does not increase telomerase expression. Last, malignant tumors overexpress telomerase, allowing them to grow indefinitely. One reason why most normal cells of the human body do not express high levels of telomerase might be to prevent cancer.
Short telomeres are a risk factor for many diseases. For example, mice with long telomeres experimentally infected with Salmonella are able to clear the infection far more efficiently than genetically identical mice with short telomeres. Also, individuals with short telomeres show a higher prevalence of adult onset diabetes, atherosclerotic lesions, and neurodegenerative diseases (like Alzheimer’s disease) as well as a higher risk for diabetic and cardiovascular disease mortality. Blackburn found that chronic psychological stress associated with caregiving resulted in increased telomere shortening. Women experiencing very high levels of perceived stress from care giving showed telomeres shorter on average, by the equivalent of one decade of additional aging compared to women experiencing low stress. Such findings may explain the earlier onset of age-related diseases in individuals who have experienced long-term, severe psychological stress. A few larger animal species that have slow or negligible senescence such as lobsters, some fish species and long-lived birds show high telomerase expression in their somatic cells.
The data on telomerase indicates it plays a role in health and aging, although there is much that is still poorly understood. For example, in general somatic cells telomerase levels are lower in larger, long-lived species than they are in smaller shorter-lived species. Additionally, some species with very long telomeres age relatively quickly, while species with shorter telomeres age much more slowly. Some species such as mice have very long telomeres and can live several generations (in mice about five) with complete ablation of telomerase activity. Last, telomerase also contributes to organism survival independently of its effects on telomere length. As yet the molecular mechanism underlying this phenomenon is poorly understood.
Thus, telomeres and telomerase are one incompletely understood component in determining the rate of aging. However, several recent studies have indicated that telomerase expression might have significant anti-aging effects. For example, aged telomerase-deficient mice with very short telomeres show neurodegeneration, testicular, splenic, intestinal atrophy, molecular pathway activation indicating significant DNA damage and a reduced olfactory function (hyposmia). Expression of functional telomerase in these mice reduced DNA damage-initiated signaling, reversed the hyposmia and increased brain size and nerve myelination. Telomerase expression also reversed the senescence-related testicular, splenic and intestinal atrophy. Thus, telomerase activity exerts not just an anti-aging effect but a rejuvenating effect, actually reversing some aspects of the aging phenotype.
Another important question is whether increased telomerase expression can slow the aging process. Studies with transgenic mice overexpressing somatic cell telomerase have not shown an increased lifespan due to the mice getting cancer. However, one recent study employing cancer-resistant mice (carrying genetic alterations in p53, p16 and ARF) showed that increased telomerase expression caused a 40 percent increase in the number of mice living to three years. Thus, telomerase expression can significantly increase the mammalian lifespan.
Although much research is needed on the basic molecular functions of telomerase, it appears that a few relatively small genetic alterations in the mammalian genome and protein expression patterns, including increased telomerase expression, can result in a significantly longer lifespan and a reduction in age-associated diseases. Thus it’s very likely that telomerase will be a major target for genetic alterations designed to increase the human lifespan, remaining a very active area in anti-aging research.