Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes

Abstract

Rationale Leucocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells (PCs) are involved in tissue repair and regeneration. Objective To examine the relationship between LTL and PCs, and their impact on adverse cardiovascular outcomes. Methods and Results We measured LTL by quantitative PCR in 566 outpatients (age 63±9 years, 76% male) with coronary artery disease (CAD). Circulating PCs were enumerated by flow cytometry. After adjustment for age, gender, race, BMI, smoking and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (p<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization or cerebrovascular events) independently of each other, with a hazards ratio (HR) of 1.8, 95% confidence interval (CI), 1.1–2.0, and a HR of 2.1, 95% CI, 1.3–3.0, respectively, comparing Q1 to Q2–4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1), had the greatest risk of adverse outcomes (HR=3.5, 95% CI, 1.7–7.1). Conclusion Although shorter LTL is associated with decreased regenerative capacity, both LTL and circulating PC levels are independent and additive predictors of adverse cardiovascular outcomes in CAD patients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.

Cholesterol efflux capacity does not associate with coronary calcium, plaque vulnerability, and telomere length in healthy octogenarians

“…However, also telomere shortening, considered a marker of biological aging, has been linked to age-related diseases such as atherosclerosis and identified as a predictor of its clinical outcomes (32). We did not find a correlation between TL and the markers of subclinical atherosclerosis flow-mediated dilation and intima-media thickness, in line with previous findings (32). In our population, we did not find an association between TL and coronary calcification as well.…”

“…We also evaluated whether serum CEC is associated with TL in our population, considering that telomere shortening, occurring with aging, has been previously related to early markers of cardiovascular disease and subclinical atherosclerosis (32,33). Similar to what observed for the parameters considered above, individuals with TL values under and over the median were not different in terms of serum CEC: average CEC ratio over standard serum was 1.44 ± 0.16 and 1.40 ± 0.18 in subjects with TL values under and over the median, respectively (ns, Figure 3).…”

Rejuvenation of Cardiac Tissue Developed from Reprogrammed Aged Somatic Cells

“…1,38 For example, Sahin et al demonstrated that Tert -/-mice exhibit early aging and heart failure. 39 It was observed in our experiments that telomere length was not significantly different between cardiac tissues harvested from newborn, adult, and aged mice, which may have been caused by maintenance of telomerase activity in aged rodents.…”

“…The aging of mammals is primarily marked by genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. [1][2][3][4][5] Before the somatic cell reprogramming era, all of the endeavors to conquer aging to rejuvenate somatic cells appeared to be insufficient. The reprogramming of mouse and human somatic cells through forced expression of defined transcription factors demonstrated that adult somatic cells could be restored to pluripotency.…”

Telomeres and Telomerase in The Aging Heart

“…(42,44) LTL represents the average TL across a heterogeneous population of leukocytes including monocytes, granulocytes and lymphocytes, and can serve as a biological marker of aging. (45) and regulation of programmed cell death. Mitochondrial dysfunction is central to theories of aging, because agerelated changes of mitochondria are likely to impair a host of cellular physiological functions in parallel and contribute to the development of all common age-related diseases.…”