Telomerase activation: A potential key modulator for human healthspan and longevity

Highlights

• Studies in animal models are available demonstrating a potential role for telomerase as anti-aging effector; evidences of a similar role for telomerase in humans is still scarce and controversial.

• Telomerase re-activation specifically in adult or old mice resulted in significant median lifespan extension without increased cancer susceptibility.

• Healthy human volunteers supplemented with TA-65, a telomerase activator, showed a better dynamics of immune system as well as an increase in several indicators of health.

• Recent studies demonstrated that statins and high Mediterranean diet adherence are associated with higher telomerase activity and lower telomeres shortening in humans.

Abstract

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases. Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.

Introduction

Ageing is a natural process characterized by a gradual decline in the function of organs and organ systems ultimately leading to an increased risk of diseases and death. Many mechanisms have been proposed to contribute to aging process. A stress response called cellular senescence, has been hypothesized to be a primary contributing factor to age-associated tissue dysfunction, reduced regenerative capacity and diseases (Hayflick, 1976, Collado et al., 2007). In fact, senescent cells have been found to increase in mice (Baker et al., 2011), primates, humans organs and tissues with increasing age, while suppressing this accumulation it has been shown to improve healthspan in mice, supporting this hypothesis (Collado et al., 2007, Herbig et al., 2006, Jeyapalan et al., 2007).

During the last 20 years, mounting evidences suggest that the progressive loss of telomeric repeats of chromosomes may function as an important timing mechanism during the aging process in various species (Campisi et al., 2001, López-Otín et al., 2013). Numerous epidemiological studies show that shorter telomeres in humans are associated with many age related diseases such as cancer, cardiovascular diseases (atherosclerosis, hypertension, myocardial infarction), cognitive decline, diabetes and overall mortality (Armanios, 2013, Fyhrquist and Saijonmaa, 2012, Epel et al., 2009).

Strikingly, patients affected by dyskeratosis congenital and idiopathic pulmonary fibrosis, display chromosomal instability and accelerated cellular senescence, particularly in tissues at high proliferative activity (Garcia et al., 2007). These hereditary diseases are caused by mutations in telomerase, a special ribonucleoprotein reverse transcriptase critical for telomere length maintenance and stability (Mason et al., 2005). While telomerase in human tissues is active only in stem and germinal cells, also a somatic cell without a functional telomerase expression shows accelerated telomere shortening and dysfunction (Hayflick and Moorhead, 1961, Harley et al., 1990).

Partial or complete loss of telomerase function dramatically accelerates aging in mice andit is associated with age-related disorders in humans (Garcia et al., 2007). Thus, it has been hypothesized that the re-activation of telomerase may represent a promising mechanism to reverse or at least delay cellular senescence, potentially leading to healthspan extension.