The first aspect to this question is whether differences in aging rates among mammalian species are caused in whole or in part by species-specific differences in telomerase/telomere biology. A very brief consideration of this question will show that this is unlikely. Mice are short-lived compared to humans, yet mice have long telomeres and adult mouse somatic cells often have telomerase activity (Blasco, 2005
). On the other hand, humans have relatively short telomeres, even when compared to closely related primates (Kakuo et al., 1999
), and telomerase activity is very low in most cells, except for some types of stem cells, the germ line, and some somatic cells such as T lymphocytes (Shay and Wright, 2007
). If telomere exhaustion were a major cause of aging one would expect humans to be relatively susceptible to this process and mice to be resistant; obviously the much longer life span of humans would suggest that differences in telomere biology is not a major determinant of life span among mammals. However, this simple argument leaves open two related questions: first, are differences in telomere biology important determinants of aging and life span among individuals within a species; and second, even if telomerase and longevity are not positively correlated, is it possible that they could be negatively correlated: could high telomerase activity be a factor causing shorter life span?
The question of whether differences in telomere biology are important determinants of aging and life span among individuals within a species is only meaningful in species such as humans that have limited telomerase activity. Nevertheless, it is possible to address the question of the consequences of shortened telomeres in tissues by engineering mice to lack telomerase activity. Mice with defects in the TERC
gene undergo generation-dependent telomere shortening. In later generation telomerase-deficient mice various organs exhibit impaired functions, demonstrating that sufficiently short telomeres do have an adverse impact on tissue function (Blasco, 2005
). However, experiments in mice cannot answer the question of whether telomeres ever reach a “critical” length, i.e. a length that impairs proliferation (or conceivably some other cellular property), in any tissue in humans during a normal life span. There is little evidence that commonly observed changes in older individuals, such as anemia and impaired wound healing, result from impaired cellular proliferation, which would be the anticipated consequence of shortened telomeres (Hornsby, 2001
). Despite the lack of clear evidence for impaired proliferation in aging there is, in fact, good evidence for progressive telomere shortening in many human cell types, including peripheral white blood cells, smooth muscle cells, endothelial cells, lens epithelial cells, muscle satellite cells, and adrenocortical cells, among others (Hornsby, 2001
). One example is of particular interest: proliferative capacity is closely related to telomere length in endothelial cells. Telomere lengths in endothelial cells decreased as a function of donor age, with a greater decline being observed in cells isolated from the iliac artery in comparison to cells from the thoracic artery (Chang and Harley, 1995
). The greater decline in telomere length was observed in the cells had likely undergone more proliferation in vivo, because they resided in a part of the vascular system where blood flow might cause most chronic damage to the endothelium. However, it is difficult to test this hypothesis directly.
Thus telomere shortening does indeed occur in the human body during aging. The question, as stated above, is whether this telomere shortening is a determinant of differences in aging and life span among individuals. Two aspects to this question are: (i) whether telomere length, as measured in specific cell populations in the body, correlates with longevity or disease; and (ii) whether telomere shortening in any cell population causes functional impairment of that cell population. At the present time the only cell populations that have been subjected to the required depth of analysis are peripheral white blood cells and some white blood cell subsets.
Several observational studies have attempted to gain insight into the question of whether age-related telomere shortening in human peripheral white blood cells is associated with health and disease status. One study concluded that “in and of itself, SES [socioeconomic status] appears to have an impact on WBC [white blood cell] telomere dynamics” (Cherkas et al., 2006
). Another study of mothers of chronically ill children concluded that “psychological stress is associated with indicators of accelerated cellular aging [including] telomere length” (Epel et al., 2004
). Both of those studies suggest an influence of perceived psychological status on telomere length. Of course, psychological stress does not necessarily cause stress at the cellular/molecular level. One plausible link is the endocrine system (Cohen et al., 2006
). Possibly the explanation for the differences in telomere length in individuals of differing psychological status lies in the actions of hormones such as glucocorticoids on cell death and cell proliferation in the hematopoietic system.
Some clinical procedures may turn out to be inadvertent experiments that address the issue of whether short telomeres in peripheral white blood cells causes functional impairment. In recipients of bone marrow transplants the hematopoietic system can suffer a dramatic telomere shortening, perhaps the equivalent to several decades of “aging” (Wynn et al., 1998
). Some data suggest that long-term survivors of bone marrow transplants may suffer immune dysfunction as a consequence of the combination of the sudden loss of telomere length at the time of transplantation followed by normal age-related shortening (Lewis et al., 2004
This area of research, i.e. epidemiological correlations between white blood cell telomere length and longevity or disease is a complex topic and a general review such as this one cannot do it justice; the topic has been the subject of an excellent recent review in this journal (Baird, 2006
). One aspect should be mentioned, and that is that overall changes in telomere length could be the result of changes in subsets of cells. In this context it is of interest that expansion of blood CD8+
T lymphocytes is associated with all-cause mortality (Wikby et al., 2002
; Pawelec et al., 2005
T lymphocytes have telomeres that are shorter than those of other white blood cells from the same individual (Monteiro et al., 1996
; Effros et al., 1996
); this may be connected to the observation that loss of CD28 expression is also associated with loss of ability of T lymphocytes to upregulate telomerase activity (Valenzuela and Effros, 2002
It must be remembered that no observational studies, whether on the entire white blood cell population or on subsets, can establish cause and effect. Such studies cannot be interpreted as indicating that shorter telomeres in some individuals (e.g. those with a higher level of psychological stress) have an adverse effect on health or mortality. In the case of both total white blood cells and T lymphocyte subsets there may be excessive cell proliferation, as a result of various causes, which then leads telomere shortening. Perhaps, short telomeres may be only an age-associated but benign or inconsequential marker, like graying of the hair or senile lentigenes of the skin. These age-related changes do result from profound alterations in melanocytes, including melanocyte stem cells (Nishimura et al., 2005
), but do not cause age-related morbidity or mortality.
There are at least three major questions that need to be answered. First, we need to know what telomere length in human tissues is associated with functional impairment, of specific organs, tissues or cell populations; second, because of the great heterogeneity in telomere lengths between cells and between different telomeres within cells, we need to know if there could be impairment of individual of cells, even if there is no measurable deficit in the cell population as a whole; and third, we do not know if telomere length in white blood cells, or T lymphocytes, correlates with telomere length in other tissues. Gaining access to appropriate tissue samples to test this is problematic. Is there a specific cell population in the body in which telomere length directly determines differences in health, disease or the actual rate of aging among individual humans? This is possible, but we have no evidence to support the existence of such a population of cells.