Telomerase activation and human health-span: an open issue

Aging Clin Exp Res DOI 10.1007/s40520-017-0766-z POINT OF VIEW Telomerase activation and human health-span: an open issue Virginia Boccardi1 · Patrizia Mecocci1 Received: 22 March 2017 / Accepted: 21 April 2017 © Springer International Publishing Switzerland 2017 Aging is a natural process characterized by the progressive decline in physiological functions, which leads to increased vulnerability to diseases and death. The old age population is increasing worldwide thanks to lengthen of life expectancy at birth, defined as the average total number of years that a human expects to live. However, while life expectancy is still rising, parameters of health-span have stagnated for years. Thus, the prevalence of age-related diseases, including neurodegenerative, cardiovascular and metabolic diseases, continues to growth with a significant negative impact on health and care systems. “Every man desired to live long but no man would be old”, said Jonathan Swift in the seventeenth century and despite many efforts in research and the large amount of described theories, we are still unable to identify hallmark of aging and far from the identification of the exact mechanisms underlying human aging. Numerous and complex are the mechanisms involved in the aging process. A sustained DNA damage response, so-called cellular senescence, has been hypothesized as one of the most important contributing factors to age-associated tissue dysfunction, reduced regenerative capacity, and, ultimately, to diseases evolution. A powerful “biologic clock”, regulated by telomere shortening, finely tunes the senescence process. Telomeres are long sequences of nucleotides located at the very end of chromosomes, which, forming together with specific proteins an end caps, are able to preserve genome stability and integrity. One of the main functions of telomeres is to keep * Virginia Boccardi virginia.boccardi@unipg.it 1 Department of Medicine, Institute of Gerontology and Geriatrics, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy chromosome ends from fraying and fusing to each other, which would destroy genetic information. Due to the end replication problem, at each cell division, telomeres lose some of their length and when they get too short and dysfunctional, a persistent DNA damage response is activated which leads the cell to senescence. Therefore, cell changes its morphology, blocked at G0 phase of cell cycle and unable to divide. However, senescence is not a singular state but rather a heterogeneous phenotype leading to diverse multiple effectors. The nuclear phenotype and patterns of gene expression are drastically altered during senescence, with down-regulation of cell cycle genes, up-regulation of senescence marker genes, and senescence-associated alteration of the secretome [reviewed in 1]. Telomerase is responsible for maintaining and elongating telomere, and consists of telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT), the catalytic component. TERT uses TERC as a template to synthesize new TTAGGG DNA repeats at a single-stranded overhang to maintain telomere length. Some cells—such as germ cells, hematopoietic progenitor cells, activated lymphocytes, and most cancer cells—show a high level of telomerase activity that overcomes telomere shortening and maintain limitless cell division and replication. In contrast to adult stem cells, which constitutively express low levels of telomerase, normal somatic human cells repress its expression immediately after birth. Inevitably, telomeres shorten at each replication event whose length represents the clock governing life countdown. Thus, for a long time, average telomere length has been considered as an indicator of cell age, individual age, and as a predictor of longevity and mortality. However, recent evidence suggested that the shortest telomeres, rather than average telomere length, are associated with age-related diseases and their rescue by 13 Vol.:(0123456789) Aging Clin Exp Res telomerase is sufficient to restore cell and organism viability [1]. A stem cell hypothesis of aging has been proposed which states that a major cause of aging is either depletion, or failed differentiation of adult stem cells, which regenerate our tissues. Similarly, to match ignition, stem cell “ignition” has to be precisely tuned to avoid the lack of proliferation, as it happens in many degenerative disorders. Given the key role of stem cells in maintenance of many tissues, it is easy to assume that they play a central role in the aging of body as a whole. This model would propose that senescent somatic cells can be easily replaced, and, as long as stem cells are functionally active, tissue aging does not occur or is partially reversible. New findings report that telomeres and telomerase are the main components of the “ignition” mechanism, which has provided an intriguing way to delay aging [2, 3]. The fact that a multi-generational study of populations with exceptional longevity exhibits abnormal circulating high telomerase activity strongly supports such hypothesis. Longer telomeres and higher telomerase activity in peripheral blood mononuclear cells (PBMC) have been also found in old age subjects from a region of the South of Italy highly adhering to Mediterranean diet and seem to be related to better health and quality of life. On the other hand, defects (mostly mutations) in core genes involved in telomere maintenance system are implicated in premature aging syndromes pathogenesis. It seems that the early stem cell depletions together with accumulation of senescent cells may trigger the onset of clinical diseases. While normal human cells in almost all tissues show progressive telomere shortening throughout life, disease risk is generally delayed until stem cells with greatly shortened telomeres cannot keep up with homeostatic tissue maintenance mechanisms [2, 3]. Thus, it is reasonable to hypothesize that the activation of telomerase in adult stem cells and, potentially, in somatic cells may be the key for tissues repair and regeneration, which may delay the onset of agerelated disease and increase years of healthy life. Despite several studies conducted in mouse animal models, evidence of a relationship between telomerase reactivation and elongation of years of health in humans are scares. The first potential telomerase activator described so far is the small molecule TA-65, derived from an extract of Astragalus membranaceous, a plant commonly used in the traditional Chinese medicine. The use of TA-65 as a treatment to improve health-span in humans has been tested in 114 volunteer subjects taking part in an open label comprehensive dietary supplementation program, which included a TA-65 dose of 10–50 mg daily. The analysis of the first year, focusing on the immune system, showed significant declines in the percent of senescent cytotoxic T cells as well as a significant reduction in the percent short telomeres in leukocytes. No adverse events were reported. 13 A subsequent study reported changes in metabolic and vascular parameters during 12 months of treatment. In addition to apparent positive immune remodeling, TA65 supplementation was associated with an improvement in markers of metabolic (fasting glucose and insulin, and total cholesterol), bone (bone mineral density), and cardiovascular health (blood pressure and homocysteine levels) [reviewed in 4]. Indeed, in a very recent study, Salvador and colleagues [4] in a randomized, double blind, placebo controlled study summarize the findings of changes of telomere length (TL) with TA-65 supplementation over a 1-year period. The study was conducted on 117 relatively healthy cytomegalovirus-positive subjects aged 53–87 years. Subjects taking the lower dose of TA-65 (250 U/ die) showed a statistical significant increase in TL, whereas subjects in the placebo group significantly lost TL. Authors concluded that such an activator could lengthen telomeres in human. Strikingly, it has been shown that PBMC telomerase activity is also responsive to lifestyle and mindset, which may represent a natural way to stimulate telomerase activity, protect telomeres from accelerated attrition, and potentially promote health-span [5]. With intensive lifestyle modification, including a low fat diet, increased physical activity, and stress reduction (by yoga, meditation, social support) [5], telomerase activity increases significantly in PBMC just after 3 months, suggesting that it is capable of immediate and short-term changes. In conclusion, studies conducted in animals demonstrated that telomerase expression through genetic modifications, viral delivery, or chemical activation results in a significant rescue of age-related diseases, but whether telomerase activation in human may be a safe approach to promote health maintenance is still unclear. Results obtained in animal constitute certainly promising opportunity for further clinical and experimental research. However, few studies conducted in small human sample populations are insufficient to make conclusions even if results are exciting. Even this opens an unprecedented door for slow-aging research, additional efforts aimed at defining the uses and the dosage of potential telomerase activators in prospective interventional studies are warranted. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Aging Clin Exp Res References 1. Martínez P, Blasco MA (2017) Telomere-driven diseases and telomere-targeting therapies. J Cell Biol 216:875–887 2. Rivera T, Haggblom C, Cosconati S, Karlseder J (2017) A balance between elongation and trimming regulates telomere stability in stem cells. Nat Struct Mol Biol 24:30–39 3. Liu L (2017) Linking telomere regulation to stem cell pluripotency. Trends Genet 33:16–33 4. Salvador L, Singaravelu G, Harley CB et al (2016) Natural product telomerase activator lengthens telomeres in humans: a randomized, double blind, and placebo controlled study. Rejuvenation Res 19:478–484 5. Boccardi V, Paolisso G (2014) Telomerase activation: a potential key modulator for human healthspan and longevity. Ageing Res Rev 15:1–5 13