Up-Regulating Telomerase And Tumor Suppressors: Focusing On Anti-Aging Interventions Part 1

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ABSTRACT CT: Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to the burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to developing strategies to impact human health at population and/or individual levels. Two different aspects of the aging process (namely, telomere shortening and DNA damage accumulation) were shown to interact in positively impacting mice median survival. However, strategies aimed at translating such knowledge into actual human health benefits have not yet been discussed. In this manuscript, we present potential exposures that are suited for population-level interventions and contextualize the roles of the population (based on behavioral exposures)and individual-level (based on small-molecule administration) anti-aging interventions in different levels of disease prevention. We suggest exposures such as moderate wine consumption. reducing calorie intake and active lifestyle is potentially useful for primordial and primary prevention, while small molecules that activate telomerase and/or tumor suppression responses are more suited for secondary and tertiary prevention(although important for primary prevention in specific populations subgroups). We also indicate the need of studying the impacts, on aging and age-related diseases, of different combinations of these exposures in well-conducted randomized controlled trials, and propose Mendelian randomization as a valuable alternative to gather information in human populations regarding the effects of potential anti-aging interventions.

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Keywords: Aging, Telomerase, Tumor suppression, Population-level interventions, Levels of disease prevention

Age-related impairments and diseases are currently among the most prevalent causes of morbidity and mortality worldwide. Conditions such as cardiovascular disease, cancer, and diabetes account for a significant portion of the burden of disease in the majority of countries since the age structure of human populations has changed and continues to change towards an increase in the proportion of the old-aged group (as a consequence of increases in life expectancy and decreases in fertility rates)[1]. Although not being the only risk factor for such conditions, the aging process itself is a fundamental and the most predictable cause of impairments that tend to occur in the elderly. Therefore, interventions that target the underlying mechanisms of the physiological aging process are promising for treatment and (at least partial)prevention of age-related diseases. There are several mechanisms evidenced to cause or favor aging, which has recently been integrated as contributing causes of the multifactorial process called aging. In this regard, the proposed aging hallmarks are mechanisms that primarily act at the molecular or cellular levels, resulting in aging at the organism level by cumulative effects of each individual factor as well as by a rather complex interplay between two or more of these [2]. cistanche penis growth In spite of recognizing the complexity and multifactorial nature of the aging process as it is currently understood, this manuscript will focus on telomere biology, and, more specifically, the interplay between telomere length and tumor suppression responses regarding adult stem cells (ASCs) function. This is justified by the fact that telomere biology is among the best established and most studied aging mechanisms, which importance can be observed in the fact that the 2009 Nobel Prize in Medicine and Physiology was awarded to the discoverers of telomerase [3]. In addition, two more aging hallmarks, as well as their interplay, are considered: DNA damage accumulation (here discussed with regards to tumor suppression responses) and ASC exhaustion; thus, at least a portion of the complex interaction between different causal factors of aging is addressed.

Telomeres, tumor suppression and ASCs in aging and cancer: an overview

Telomeres are guanine-rich (5' TTAGGGG 3') DNA repeats in tandem located at the ends of eukaryotic chromosomes in association with a protein complex called shelterin [4]. Telomere integrity is essential to prevent chromosome ends from being recognized as double-strand DNA breaks and from being fused together [5]. Due to the incapacity of the cellular machinery to replicate the very ends of linear chromosomes (i.e., the end replication problem)[6] and to other phenomena such as oxidative stress [7], telomeres are shortened after each cell division. In some cell types - including embryonic stem cells, germline stem cells, and ASCs-the activity of a ribonucleoprotein complex called telomerase counteracts telomere shortening by elongating these structures through de novo reverse transcription [8, 9]. Telomerase is mainly composed of two subunits: the telomerase reverse transcriptase (encoded by TERT -EntrezGene ID:7015), of which expression is the main rate-limiting factor for telomerase activity (since the other component is found at varying levels in several tissues). This subunit catalyzes the reaction based on an RNA template called telomerase RNA component (encoded by TERC-EntrezGene ID:7012). Telomere dysfunction (caused by progressive telomere shortening or telomere uncapping) triggers tumor suppression responses (apoptosis and/or senescence), thus limiting cell viability. In ASCs, telomerase levels are sufficient only to delay telomere shortening [10], resulting in ASCs eventually reaching a critical telomere length state with time. Considering the fundamental roles of ASCs in the maintenance of organism homeostasis by promoting tissue self-renewal, telomere shortening plays a major role in organism aging and age-related diseases by limiting ASCs viability. cistanche salsa benefits Indeed, an elegant study using transgenic mice showed that removing senescent [ie., pl6(Ink4a)-positive] cells can extend healthspan not only by preventing or delaying tissue dysfunction but also by alleviating already established age-related impairments [11].

Many age-related conditions were evidenced to have telomere dysfunction as an important causal factor Indeed, a collection of telomere-related disorders recently termed "telomere syndromes" was proposed as important for understanding age-related diseases[12]. In this regard, it is important to note that telomere biology also plays a critical role in cancer. The genomic instability caused by telomere dysfunction highly predisposes the accumulation of mutations and, consequently, acquiring tumorigenic characteristics [13]. Moreover, telomerase activity is the main immortalization mechanism of tumors (being present in approximately 85%-90%of human cancers)[14,15], thus being a highly prevalent cancer biomarker. In fact, both telomere dysfunction and telomerase activity are regarded as two cancer hallmarks [16]. Therefore, the exposure illustrates the interplay between telomere biology and tumor suppression in age-related impairments (especially regarding tissue self-renewal failure) and cancer, with the capacity of the tumor suppression machinery to sense critically shortened telomeres playing a crucial role in the"balance" between these two age-related conditions with regards to telomere dysfunction. Such interplay was discussed in more detail elsewhere in the context of dyskeratosis congenital(a telomere syndrome)[17].

Telomere length and tumor suppression: potential anti-aging effects

One of the earliest notions that chromosome ends were somehow related to the capacity of cells to divide in vitro was formalized in a theory of in vitro aging published more than 30 years ago [18]. Among the earliest solid experimental evidence for the role of telomeres in aging, in vitro studies of human fibroblasts can be cited, which showed that telomere shortening occurs during serial passages [19] and that initial telomere length predicts the capacity to replicate in vitro [20]. It is important to note that, by that time, the roles of tumor suppression in inducing telomere shortening-dependent senescence (which was shown to depend on DNA damage checkpoint proteins,suchasp53 and RB-encoded by TP53 and RB1; EntrezGene ID:7157 and 5925, respectively) were already being recognized [21]. cistanche tubulosa dosage reddit Subsequently, it was shown that introducing TERT expression reconstitutes telomerase activity and extends the lifespan (concomitantly with longer telomeres, vigorous cell division, and reduced senescence) of normal human cells in vitro [22-24].

Although several studies of different natures could be cited, two landmark studies in mice provided invaluable evidence relevant to this discussion. One of them used an elegant genetic engineering strategy that allowed inducible reactivation of TERT in late-generation telomerase-null mice(ie., telomere-deficient animals)to show that telomerase can reverse age-related tissue degeneration in several organs(e.g., testes, spleen, and intestines), notably including the neural tissue(which is considered a low-turnover tissue)[25]. The other study combined constitutive TERT expression in epithelial tissues (i.e., under the regulation of the KRT5 EntrezGene ID: 3852 - promoter) and increased expression (under their normal regulation) of tumor suppression genes [namely, CDKN2A (EntrezGene ID:1029)-encoding the proteins p16 and Arf-and TP53], resulting in long-lived cancer-resistant mice called SUPER-M. cistanche แอ ม เว ย์ These mice were used to assess the longevity effects of telomerase in a cancer-resistant background (which is important given the cancer risk associated with constitutive telomerase activity).In both overall and cancer-free mice, a clear effect of telomerase in extending median survival was observed [26]. Furthermore, it is important to consider that the increased expression of tumor suppression genes in mice had been already shown to be protective against aging [27], which is in accordance with the notion that tumor suppressors restrain ASCs proliferation (thus delaying their exhaustion) and have been evidenced to reduce or prevent the accumulation of ASCs with DNA damage [28].

In addition to the fact that the SUPER-M mice study represented a major contribution to the understanding of telomerase and tumor suppression in aging and cancer, a more detailed observation of the median survival results (as presented in a subsequent publication [29])reveals that telomerase and tumor suppression are effect modifiers of each other in both overall and cancer-free animals(Table 1). Indeed, such effect modification could already be detected by comparing median survival differences of TgTERT-Sp53 with SUPER-M-cancer-resistant mice, with the last showing a much greater difference(and, then, a stronger effect of telomerase)than the first. how much cistanche to take However, based on table 1, it can also be noted that the same occurs for tumor suppression (ie., it has a much greater effect on median survival when occurs concomitantly with constitutive telomerase activity in the epithelial).

Importantly, the values in table 1 also indicate [although the median survival in the SUPER-M mice (comparing with Sp53 mice)was greater for cancer-fee animals] that adding TgTERT in a cancer-resistant background has similar if not slightly higher effects on overall median survival. Such observation allows the speculation that, if combined with cancer resistance, increases in telomerase activity (at the very least) do not increase cancer risk, and might even have modest anti-cancer effects. On the other hand, the observed differences in median survival of overall and cancer-free animals when comparing SUPER-M and Sp53 mice could simply indicate that such an increase in lifetime implicates cancer is an important cause of death even in a background of telomerase and tumor suppression up-regulation. Such rationale is in accordance with the multifactorial nature of cancer (with many hallmarks other than telomere dysfunction and DNA damage/mutation accumulation)[16] and the notion that tumorigenic telomerase activation is commonly regarded as a relatively late event in carcinogenesis, possibly occurring a consequence of the genomic instability caused by, for example, telomere dysfunction [13].

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