Telomere dysfunction markers as biomarkers of aging

How old are you? At present, the best experimental approach to that question is to inspect your driver’s license; we are very good at measuring chronological age, but far worse at measuring physiological age. Understatement alert: It would be nice to have access to a biological measurement (or series of measurements) that allowed us to determine an individual’s age.

Until we have such a tool, questions like “how rapidly is this individual aging?” and “is this treatment having a positive effect on the rate of aging?” will be meaningless. Therefore, biogerontologists interested in measuring the rate of aging are stuck with lifespans, which are rather limited in their utility: They’re population measurements, for one thing, which means that it’s extremely difficult to study differences between rare natural variants and the population overall. Furthermore, they’re necessarily retrospective, which means that by definition any study that uses lifespan as an endpoint will be unable to benefit its subjects (because they will already be dead).

So, the race is on to find useful biomarkers of aging, which could be used to assess physiological age and (by comparing physiological to chronological age) help us ask meaningful questions about the rate of aging in different individuals.

Telomere length is a tantalizing biomarker for the aging process: it’s positively correlated with life expectancy and negatively correlated with stress and disease.

If telomere shortening is a biomarker of aging, then the measurable consequences of telomere shortening should also function as biomarkers, i.e., aging bodies should contain high levels of factors secreted by cells with dysfunctional or critically short telomeres. According to a recent paper by Jiang et al., this is indeed the case:

Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc−/−). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc−/− mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to γ-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.

The assay is performed on plasma, rather than peripheral blood lymphocytes (which is where a lot of direct measurements of telomere length are made; this is not because PBCs are more interesting than, say, fibroblasts, but rather because they’re easier to get to). Granted that plasma doesn’t comprehensively represent the secretory output of every cell in the body, this assay almost certainly represents a better sampling than others that focus on a single cell type — by looking at soluble secreted proteins, the assay approximates a measurement of the “consensus” of cells throughout the whole body.

The proteins identified here accumulate with age — and, appropriate of the conversation at the top of the post, they accumulate faster in subjects who are both aged and suffering from age-related disease; in other words, in people whom we might intuitively assign to the “more rapidly aging” category. As proteomics and detection technology advance, approaches like this may bring us much closer to the meaningful measurement of physiological age.


  1. the problem is that it´s not as straightfoward as a countdown clock, at least not by itself.

    In one article by Dr. Rita Effros I read that lymphocites (I think her experiments were with TCD8?) get telomerase triggered two times, when faced with an antigen, but after that they stopped responding to that. Maybe there is a second underlying clock underneath? (maybe the accumulation of some protein? that would explain why Cuervo´s experiments with protein clearance -assuming there was no confusion associated to diet, which is something that has been biting me ever since I saw that line in the news articles about “the expression being triggered by a change in diet”- were apparently fruitful?)

Comments are closed.