Up-Regulating Telomerase And Tumor Suppressors: Focusing On Anti-Aging Interventions Part 2

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Population-level interventions based on telomerase and/or tumor suppression up-regulation

The literature exposed so far(although insufficient as a comprehensive review) provides solid evidence for the potential of up-regulating telomerase and tumor suppressors to reduce the risk and/or ameliorate the gravity of age-related diseases, especially with regards to tissue/organ degeneration (which has loss of tissue self-renewal capacity due to ASC exhaustion as a key causal factor). In humans, implementing such interventions is a non-trivial challenge, involving several individual and population(including biological/medical, socioeconomic, and political) factors. what is a cistanche In spite of this complexity, it is evident that certain interventions that would be highly useful in the clinical setting (e.g., for treatment purposes)would not even be feasible for reducing the risk of age-related diseases in an entire group of people in the population level (and vice-versa)? It is hardly arguable that, at the population level, interventions aiming at preventing or reducing disease risk are preferable over therapeutic approaches. bioflavonoids Moreover, preventive strategies are normally cheaper and easier to implement by health planning and policies. The most common and illustrative examples are interventions related to dietary or exercise habits. Since these are, in essence, behaviors, they can be influenced at the population level by mass-targeted strategies, such as educational campaigns, economic policies (e.g, making healthy food products more accessible), and infra-structure initiatives (e.g, bike paths).

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Resveratrol

Regarding telomerase activity, there are examples of both dietary and exercise-related interventions with great potential to be applied at the population level. Perhaps one of the most popular examples is resveratrol, although definitive results are yet to be obtained. There is, however, evidence for a benefic role of this phenol in human health by delaying aging. Taking atherosclerosis as an example, TERTexpression was shown to be activated by resveratrol treatment in a dose-dependent manner in endothelial progenitor cells in vitro, which was accompanied by an inhibition of in vitro endothelial progenitor cells senescence onset [30]. Furthermore, there is evidence that resveratrol treatment can immortalize p53-deficient cells, thus reinforcing the importance of effective tumor suppression responses in counteracting potentially tumorigenic consequences of telomerase up-regulation [31]. The relevance of these findings is highlighted by the evidence for causal roles of telomere shortening in atherosclerosis[32] and that TERT up-regulation has been discussed as a potential strategy to promote angiogenesis for tissue engineering applications [33].

The translation of the potential benefits of resveratrol into actual health gains for the population would depend on, for example, incorporating such substances into the diet. In this regard, red wine and oral administration of resveratrol in normal rats have been shown to preserve vascular function by delaying its aging, although no differences in lifespan were observed [34]. Importantly, a reduction in p53 levels was also observed, which raises a concern regarding cancer risk associated with resveratrol. In this regard, a study using cancer cell lines reported that resveratrol treatment activates the p53 pathway [35]. Such controversy can be speculated to be attributable to the markedly different physiological states of the biological systems where the experiments were performed. It is plausible to hypothesize that, while in cancer cell lines resveratrol activates the p53 pathway in response to a cellular environment with high levels of stress and genomic instability, in normal rat cells there would be no such "triggering signaling" for the p53 pathway. buy cistanche Therefore, p53 levels in normal rat cells could be diminished as a rather indirect consequence of the healthier cellular environment state induced by resveratrol administration (such a hypothesis, although plausible, requires experimental confirmation). Nevertheless, resveratrol is a potential candidate for delaying the onset of age-related diseases at the population level (possibly through wine consumption) in the context of telomerase and tumor suppression up-regulation. In fact, it has been shown that resveratrol increases lifespan and promotes physiological benefits for middle-aged mice on a high-calorie diet [36], thus possibly being a benefic intervention even for individuals with bad dietary habits and/or obesity.

Caloric/dietary restriction

Calorie intake is a crucial aspect of diet, with important implications for different human health states, including increasing the risk for several age-related diseases. Interestingly, caloric restriction (sometimes referred to as dietary restriction, which consists of reducing total calorie intake while maintaining adequate nutrition) has been evidenced to increase lifespan and reduce the risk of age-related diseases (including cancer)[37. Different from resveratrol, the benefits of caloric restriction for healthier aging have been exhaustively investigated and demonstrated in different species and contexts, including normal and disease states (as reviewed elsewhere [38]). However, it is important to note that this intervention is not universally acknowledged as effective in humans[39]. Indeed, the effects of caloric restriction have been evidenced to depend on aspects such as genetic background [40] and the phase of life when it occurs [41-44].

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Considering the evidence linking caloric restriction with aging, it is somehow intuitive to investigate the roles of telomere biology in such a relationship. However, evidence in this context is relatively scarce. A negative association between telomere activity (and cell proliferation)and caloric restriction has been reported in a study on hepatic cells of mice pre-treated with aflatoxin BI[45], which is known to induce DNA damage and considered an important risk factor for hepatocellular carcinoma [46]. In a more recent study on normal and immortalized fetal lung fibroblasts, glucose restriction has been shown to inhibit growth, induce apoptosis and decrease TERT expression in the last, but to extend lifespan and up-regulate TERT in the former, and that such differential impacts on TERT expression were partially mediated by epigenetic mechanisms [47]. This study, then, provided evidence that glucose (and possibly caloric) restriction may have both anti-cancer(when occurring in cancer or precancerous cells) and anti-aging effects(in normal cells), with different consequences regarding telomerase regulation depending on the cellular and pathological context. In the same year, another study (in mice) found that adult-onset, short-term caloric restriction reduces the number of senescent cells in the small intestinal epithelium and liver in association with improved telomere maintenance in the absence of telomerase up-regulation [48]. Evidence for a role of caloric restriction in up-regulating telomerase activity by increasing the levels of TERT expression has been recently reported in mice, in addition to a synergic role between telomerase and caloric restriction in mice healthspan and longevity [49]. The studies discussed above are in accordance with the theory that caloric restriction protects against DNA damage by restraining the metabolism [50, 51], thus extending lifespan by reducing DNA damage accumulation(which is a hallmark of aging [2]). cistanch Considering that DNA damage accumulation is also a cancer hallmark [16], caloric restriction is suggested to partially mimic a cancer-protective environment and, therefore, would be expected to interact with telomere maintenance in regulating aging and age-related impairments given the findings of the SUPER-M mice study [26] and another piece of evidence(as reviewed elsewhere [17). Such expectation has been, indeed, observed experimentally by subjecting transgenic mice over-expressing TERT to caloric restriction [49]. cistanche Australia Furthermore, both rapamycin and metformin (two substances that have been suggested to act as caloric restriction mimetics [38]) have been evidenced to up-regulate tumor suppression responses(as reviewed elsewhere[52]). Thus, the notion that caloric restriction has both anti-cancer and anti-aging properties may be explained by the up-regulation of tumor suppression responses by this intervention (in addition to the recent evidence for a role in increasing TERT expression), thus either inducing senescence and/or apoptosis in cancer cells or extending healthspan in normal cells.

Physical activity

The awareness of the benefits of physical activity for human health is widespread not only in the media and general culture but also in the scientific literature. The public health potential of promoting physical activity is hardly arguable since physical inactivity has been shown to be an important risk factor for several chronic diseases and to reduce life expectancy worldwide [53]. Importantly, physical inactivity prevalence tends to increase with age, probably as a consequence of conditions such as sarcopenia(which is, in turn, ameliorated by physical activity)[54-56].

The well-established benefits of physical activity for lifespan and health(especially regarding chronic diseases)raise the possibility of a role for telomere biology. In a study of protective cardiac effects of physical activity, it was shown that both short and long-term voluntary exercise increase cardiac 7ERTexpression and telomerase activity in mice, which was evidenced to be a mediator of such benefits [57]. More recently, long-term effects of exercise(over a 1-year period) on mice(8 weeks old at baseline)on telomere dynamics have been evaluated. Although the exercise was observed to reduce telomere shortening in the liver and cardiac tissues, opposite effects were found in skeletal muscle. Notably, telomerase activity was up-regulated by exercise in skeletal muscle but did not change in neither liver nor cardiac tissues [58]. Importantly, a recent randomized controlled trial of qigong exercise(4-month intervention in 64 patients with chronic fatigue or chronic fatigue syndrome)showed increased telomerase activity in peripheral blood cells [59], thus providing important evidence for a causal role of physical activity in telomere biology. Regarding tumor suppression responses, although there is some evidence for an up-regulation effect associated with physical activity, the literature is scarce. The acute exercise was shown to activate AMPK (encoded by PRKAAI and PRKAB1; Entrez gene ID: 5562 and 5564, respectively)and p38 MAPK(encoded by MAPK14; EntrezGene ID:1432)phosphorylation in skeletal muscle biopsies from young males(n=6)[60], suggesting that p53 activation could also be occurring [61,62]. Indeed, a more recent study in 10 active men compared two different physical activity protocols and obtained similar results, with increased phosphorylation of AMPK, p39 MAPK, and p53 in skeletal muscle biopsies [63].

Final remarks and conclusions

In this manuscript, three commonly studied interventions with the potential to be translated into population-level anti-aging strategies were pointed out and briefly discussed. It is important to note that proper evaluation of the existing evidence regarding anti-aging interventions that impact telomere lengthening and/or tumor suppression would require an extensive systematic review. The aim of the present manuscript, however, was to present the concept of transposing the knowledge obtained from the SUPER-M mice study into actual public health benefits based on scientific literature. It is also worth noting that the manuscript focused on interventions suited for population-level strategies, although interventions more suited for individual-level application are also important, especially in the clinical setting. Examples of such interventions would be telomerase activators (eg., TA-65° [64-66], food supplement 20070721-GX [67], GRN510 [68],astragaloside IV and cycloa stragenol [69,70]) and MDM2(a p53 inhibitor, encoded by MDM2; EntrezGene ID:4193)inhibitors [71-74] to improve telomere maintenance and up-regulate tumor suppression responses, respectively.

Indeed, individual-level interventions aimed at up-regulating telomerase and tumor suppression responses would have several applications. The most obvious would be to treat age-related diseases, such as cancer or impairments caused by ASC exhaustion. This application can be easily extended to the prevention of further development of diseases diagnosed in the early stage, thus evidencing the potential of such interventions for both secondary and tertiary levels of disease prevention [75]. Additionally,individual-level interventions would be applicable at the primary level of disease prevention in the context of the"high-risk-individual strategy" in two distinct manners. One would be to promote an acute anti-aging effect (to be followed by population-level strategies) to counteract either the side effects of therapeutic approaches that the individual had been submitted to(e.g, chemotherapy, which has been evidenced to induce both telomere shortening and DNA damage[76,77)or the negative effects of behaviors such as heavy smoking(which is considered to accelerate telomere shortening [78, 79]). The other application would be to reduce disease risk in susceptible individuals (e.g., carriers of highly penetrant disease-associated genetic profiles). Individual-level interventions would also be useful in population sub-groups where the population-level interventions available would be not feasible and/or harmful/controversial. For example, stimulating physical activity is less effective(or even not effective) for individuals with a premature physical disability or congenital defects that imposes major difficulties for doing regular physical activity (especially in individuals of low socioeconomic position). Another example is a caloric restriction in the elderly due to the risk of favoring muscle mass loss [38]. A summary of the applications of population-level and individual-level interventions aimed at up-regulating telomerase and tumor suppression responses is provided in figure 1. In spite of the important applications of individual-level anti-aging interventions, public health strategies benefit more from population-level interventions. In this manuscript, we suggest that resveratrol (mainly through wine consumption), caloric restriction, and physical activity are exposures with a potential anti-aging effect regarding telomere maintenance and tumor suppression responses. In order to obtain further evidence in human populations, an interesting strategy would be to employ Mendelian randomization using genetic markers in genes involved in pathways related to those interventions(e.g., mTOR SNPs as caloric restriction proxies and ALDH2 SNPs in populations where wine is the most consumed alcoholic beverage-as wine consumption proxies)as instrumental variables as an attempt to gather robust causal evidence (assuming the requirements of Mendelian randomization are met) [80]. Nevertheless, more definitive assessments depend on well-conducted randomized controlled trials. In this regard, it would be particularly important to have the groups randomized to receive different combinations of each strategy in order to understand how they act together in impacting aging and age-related diseases. Finally, given the multifactorial nature of aging, interventions that target factors other than telomere maintenance and tumor suppression responses are important to be considered and studied in order to elaborate on the most appropriate population and individual-level anti-aging interventions.

This article is extracted from Aging and Disease • Volume 5, Number 1, February 2014