The Nine Central Hallmarks of Aging
The scientific community on biogerontology and geroscience is more or less in unison with the following hallmarks of aging that are briefly described below and which will be better developed during the power point presentation. They were summed up and developed in an article written by Carlos Lopez-Otin et al and published in the peer reviwed Journal “Cell” in 2013 (The hallmarks of aging, Cell, June 2013, 153 (6); 1194-1217). However, not all scientists agree on all of the causes that explain these nine hallmarks of aging, and in particular, the hierarchy of causation (which causes are the most important)..
1. Genomic instability.
Genome instability is defined as higher than normal rates of DNA mutation. Mutation is not necessarily bad, but under the circumstances of today, it is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. But as we see today, genomic instability has catastrophic consequences for age-related diseases such as cancer and other chronic diseases as well as accelerated aging.
In terms of causation, mutations arise either from the molecular inactivation of DNA repair pathways or as a result of an overload of genotoxic stress from cellular processes such as transcription and replication that overwhelm high-fidelity DNA repair. As we will see in the power point presentation, exposure to external genotoxic agents (pollution) is a huge driver to genomic instability. (Annu Rev Genet. 2013;47:1-32. Source)
2. Mitochondrial DNA Break-down & Dysfunction
Mitochondrial function has a profound impact on the aging process. As cells and organisms age under non holistic conditions, the efficacy of the respiratory chain tends to greatly diminish, thus increasing electron leakage and reducing ATP generation. This mitochondrial decline is especially noticeable in tissues with high energy demand such as the heart and the brain. In this context, mutations and deletions in aged mtDNA contributes all the more to aging that the oxidative microenvironment of the mitochondria lacks protective histones in the mtDNA. (Human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16,569 bp and contains 3 genes encoding 13 proteins, 22 tRNAs, and 2 rRNAs. Recent mitochondrial transcriptome analyses revealed the existence of small RNAs derived from mtDNA). Likewise with the gradual erosion of the mtDNA repair mechanisms.
In eukaryotic (human) cells, most of the genetic material is nuclear, stored in the nucleus of the cell, where it is strongly protected. On the other hand, the genetic material within these bacteria-derived mitochondria is less protected. Hence, their significant contribution to both chronic diseases and accelerated aging. The loss of AMPK expression as well as Telomere Length and TERT (telomerase) loss have also been associated with mitochondrial biogenesis dysfunction. (Source)
3. Telomere Shortening and Telomerase Depletion
Normal aging is accompanied by telomere attrition in mammals. Which means, the more somatic cells divide, the less long are telomeres. Once this cellular division reaches what is called the Hayflick peak or limit, they go into Sencescence. Molecularly, telomeres are short sequences of nucleotide repeats found at both ends of each chromosomes. Telomere length shortens with each cell division, which contributes to the normal process of cellular aging and sets an upper limit on cell lifetimes.
Telomeres provide genomic stability to normal cells and act as a tumor suppression mechanism. (Source). Telomere shortening takes place faster in animals that age faster than those that age slowly. Likewise with Proregia children where pathological telomere dysfunction dramatically accelerates their aging. On the other hand, the experimental stimulation of telomerase delays aging in both mice as well as in human cells in vitro. In Longevity medicine, the more one’s telomeres are maintained in good shape, in general, the longer he or she can extend lifespan. However, there are a few new findings that redefine the longevity implications of telomerase. In this Presentation, we will review telomere biology and where we are at in terms of whether or not this pathway is the Core aging pathway we are looking for.
4. Epigenetic Alterations
The epigenome appears to be the master program which controls the expression of the genetic code by switching off and on genes and their proteins. There are multiple lines of evidence suggesting that aging is accompanied by epigenetic switches and that epigenetic perturbations can provoke, among other examples, progeroid syndromes in model organisms.
Furthermore, SIRT6 exemplifies an epigenetically relevant enzyme whose loss-of-function reduces longevity and whose gain-of-function extends longevity in mice (Kanfi et al., 2012; Mostoslavsky et al., 2006). Collectively, these works suggest that understanding and manipulating the epigenome holds promise for improving age-related pathologies and extending healthy lifespan. (Talens et al., 2012). In this Presentation, we will see more in detail how epigenetic changes involve alterations in (a) DNA methylation patterns, (b) post-translational modification of histones, and (c) chromatin remodeling.
5. Loss of Proteostasis
The decline in the protein quality of our cells, called the loss of protein homeostatis or proteostasis, is a fundamental mechanism of aging. (Powers et al., 2009). Even though our bodies have defenses against cellular stress, after decades of repeated assaults by stressors such as free radicals, waste material and toxins, the proteins in our cells become damaged. As a result, they misfold. Amyloidosis from which many supercentenarian die is a misfoldment of protein problem All cells take advantage of an array of quality control mechanisms to preserve the stability and functionality of their proteomes.
Proteostasis involves mechanisms for the stabilization of correctly folded proteins, most prominently the heat-shock family of proteins, and mechanisms for the degradation of proteins by the proteasome or the lysosome (Hartl et al., 2011; Koga et al., 2011; Mizushima et al., 2008). The activities of the two principal proteolytic systems implicated in protein quality control, namely, the autophagy-lysosomal system and the ubiquitin-proteasome system, decline with aging (Rubinsztein et al., 2011; Tomaru et al., 2012), supporting the idea that collapsing proteostasis constitutes a common feature of old age. However, there are holistic and genetic ways to to improve proteostasis.
6. Deregulated Nutrient-sensing
The “deregulated nutrient sensing” was the first hallmarks to be described to influence aging in animals, through the insulin and IGF‐1 signaling pathway (IIS) (Kenyon, 2005). IGF‐1 is produced by several cells types (mainly hepatocytes) in response to GH release from the anterior pituitary. IGF‐1 has been shown to trigger the same intracellular signaling pathways stimulated by insulin. The IIS pathway is the most evolutionarily conserved pathway of aging, shown to modulate lifespan in model organisms across a great evolutionary distance from Caenorhabditis elegans to mice (Kimura et al., 1997; Tatar et al., 2001; Fontana et al., 2010; Kenyon, 2010b; Mercken et al., 2013). Accordingly, genetic polymorphisms/mutations that cause loss of function of GH, IGF‐1 receptor, insulin receptor or its downstream factors, have been implicated in human longevity as in model organisms (Fontana et al., 2010; Kenyon, 2010b; Tazearslan et al., 2011; Barzilai et al., 2012; Milman et al., 2014). Dietary restriction is a well‐known environmental signal shown to expand lifespan in eukaryote species, from yeast to primates (Colman et al., 2009; Fontana et al., 2010; Mattison et al., 2012).
The “longevity response” to dietary restriction is regulated by several nutrient‐sensing pathways: the kinase TOR, AMP kinase, sirtuins, and the IIS (Kenyon, 2005). Current available evidence supports the idea that anabolic signaling accelerates aging, and decreased nutrient signaling extends longevity (Fontana et al., 2010). Even more, a pharmacological manipulation that mimics a state of limited nutrient availability, such as rapamycin, can extend longevity in mice (Harrison et al., 2009). In other words, less is more when it comes to this signaling pathway, as shown with worms, flies and mice (Fontana, op cit.) In addition to the IIS pathway that participates in glucose-sensing, there are three other pathways to the nutrient-sensing systems: mTOR, for the sensing of high amino acid concentrations; AMPK, which senses low energy states by detecting high AMP levels; and sirtuins. In Holistic medicine, we have techniques to help modulate these pathways.
7. Cellular Senescence
When telomeres shorten, cells can’t divide anymore, at which point they become senescent. When we are vibrant, senescent cells are thought to be cleared by the immune system, but when we are older, they stick around secreting harmful inflammation molecules and sticking to healthy cells. Canakinumab was manufactured to dampen this senescence inflammation called infammaging. But this drug has its limits. On the other hand, with holistic medicine, we have tools to assist in the removal of these inflammatory pro-aging senescent cells. (Source)
Technically, cellular senescence can be defined as a stable arrest of the cell cycle coupled to phenotypic changes (Campisi and d’Adda di Fagagna, 2007; Collado et al., 2007; Kuilman et al., 2010) This phenomenon was originally described by Hayflick in human fibroblasts serially passaged in culture (Hayflick and Moorhead, 1961). Today, we know that the senescence observed by Hayflick is caused by telomere shortening (Bodnar et al., 1998), but there are other aging-associated stimuli that trigger senescence independently of this telomeric process. Most notably, non-telomeric DNA damage and de-repression of the INK4/ARF locus, both of which progressively occur with chronological aging, are also capable of inducing senescence (Collado et al., 2007).
In addition to DNA damage, excessive mitogenic signaling is the other stress most robustly associated to senescence. A recent account listed more than 50 oncogenic or mitogenic alterations that are able to induce senescence (Gorgoulis and Halazonetis, 2010). All in all, cellular senescence appears to be a beneficial compensatory response to damage that becomes deleterious and accelerates aging when tissues exhaust their regenerative capacity. It’s been shown that a moderate enhancement of the senescence-inducing tumor suppressor pathways appears to be able to extend longevity (Matheu et al., 2009; Matheu et al., 2007), and, at the same time, elimination of senescent cells in an experimental progeria model has delayed age-related pathologies (Baker et al., 2011). Therefore, two interventions that are conceptually opposite are able to extend healthspan. In this Presentation, we will examine the four phases of cellular senescence and conclude with a work on their relevance insofar as optimal longevity is concerned.
8. Stem Cell Exhaustion
Stem cell exhaustion unfolds as the integrative consequence of multiple types of aging-associated damages and likely constitutes one of the ultimate culprits of tissue and organismal aging. The decline in the regenerative potential of tissues is one of the most obvious characteristics of aging. For example, hematopoiesis declines with age, resulting in a diminished production of adaptive immune cells, a process termed immunosenescence, and in an increased incidence of anemia and myeloid malignancies (Shaw et al., 2010). A similar functional attrition of stem cells has been found in essentially all adult stem cell compartments, including the mouse forebrain (Molofsky et al., 2006), the bone (Gruber et al., 2006), or the muscle fibers (Conboy and Rando, 2012). Studies on aged mice have revealed an overall decrease in cell cycle activity of hematopoietic stem cells (HSCs), with old HSCs undergoing fewer cell divisions than young HSCs (Rossi et al., 2007). This correlates with the accumulation of DNA damage (Rossi et al., 2007), and with the overexpression of cell cycle-inhibitory proteins such as p16INK4a (Janzen et al., 2006).
As we oxidize (ie, age by losing electrons) our stem cells eventually lose their ability to divide and thus go into decline, at which point our bodies are unable to replace the stem cells that have migrated, differentiated, or died. Hence, the increase of age-related disorders, if only because the main function of stem cells is to replace damaged tissues. Because stem cell exhaustion is an important hallmark of aging, geroscientists are working on attempts to rejuvenate stem cells. Promising studies suggest that stem cell rejuvenation may reverse the aging phenotype at the organismal level (Rando and Chang, 2012). Integrative and regenerative medicine focuses on the early “banking” (storage) of stem cells that can be inoculated to worn out tissues when needed. Holistic medicine’s focus is on preserving and boosting one’s own stem cells. (Source)
9. Altered Intercellular Communication
Beyond cell-autonomous alterations, aging also involves changes at the level of intercellular communication, be it endocrine, neuroendocrine or neuronal (Laplante and Sabatini, 2012; Rando and Chang, 2012; Russell and Kahn, 2007; Zhang et al., 2013). As a consequence, neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) tends to be deregulated in aging as inflammatory reactions increase, immuno-surveillance against pathogens and premalignant cells declines, and the composition of the extracellular environment changes, thereby affecting the mechanical and functional properties of all tissues.
A prominent aging-associated alteration in intercellular communication is ‘inflammaging’, i.e. a smoldering pro-inflammatory phenotype that accompanies aging in mammals (Salminen et al., 2012). Inflammaging may result from multiple causes such as the accumulation of pro-inflammatory tissue damage, the failure of an ever more dysfunctional immune system to effectively clear pathogens and dysfunctional host cells, the propensity of senescent cells to secrete pro-inflammatory cytokines (see section on Cellular Senescence), the enhanced activation of the NF-κB transcription factor, or the occurrence of a defective autophagy response and SIRT6 may also down-regulate the inflammatory response through deacetylation of NF-kB subunits and transcriptional repression of their target genes (Kawahara et al., 2009; Rothgiesser et al., 2010).
Beyond inflammation, accumulating evidence indicates that aging-related changes in one tissue can lead to aging-specific deterioration of other tissues, explaining the inter-organ coordination of the aging phenotype. In addition to inflammatory cytokines, there are other examples of ‘contagious aging’ or bystander effects in which senescent cells induce senescence in neighboring cells via gap junction-mediated cell-cell contacts and processes involving ROS (Nelson et al., 2012). The microenvironment contributes to the age-related functional defects of CD4 T cells, as assessed by using an adoptive transfer model in mice (Lefebvre et al., 2012). Likewise, impaired kidney function can increase the risk of heart disease in humans (Sarnak et al., 2003).
Summary on the First Nine Hallmarks
The common characteristic of the first four hallmarks is the fact that they are all pretty much delerious to the body’s ability self-repair and thrive. This is the case of DNA damage, (including chromosomal aneuploidies), mitochondrial DNA mutations, telomere loss, epigenetic drift, and defective proteostasis. These hallmarks are often initiating and their damaging events progressively accumulate with time.
The next hallmarks appear to generate compensatory mechanisms that can mitigate the nefarious effects of the first hallmarks. However, while at low levels, they mediate beneficial effects, at high levels, they can become deleterious. This is the case for senescence, which protects the organism from cancer, but in excess promotes protein misfoldment and aging. Similarly, reactive oxygen species (ROS) mediate cell signaling and survival, but at chronic high levels produce cellular damage. And while optimal nutrient-sensing and anabolism mechanisms are key for survival, in excess then become counter-productive. These hallmarks can be viewed as designed for protecting the organism from damage or from nutrient scarcity, but when exacerbated or chronic, they generate further damage.
As for the last two hallmarks, stem cell exhaustion and altered intercellular communication, these can further messed up the body’s integrity by impacting its entire tissue homeostasis system. Notwithstanding the interconnectedness between all of these hallmarks and their evolutionary “conspiracy” to bury the host, happiness and holistic medicine can attenuate some of these mechanisms while reversing othe
Evidence of a correlation between Longer Telomeres and Life expectancy.
Do people with longer telomeres have longer life expectancy? In 2003, Richard Cawthon of University of Utah first addressed this question experimentally with a study that was clever, innovative and courageous.ççç
It was innovative in that he introduced a fast and convenient way to measure telomere length from very small quantities of DNA, using the Polymerase Chain Reaction. It was clever in that, instead of a “prospective study” measuring telomere length in his subjects and then following 20 years to see what would happen to them, he did the experiment retrospectively, using historic samples of blood that had been taken from people twenty years earlier and kept in frozen storage by a local hospital. And it was courageous in that everyone believed at the time that extending life could not be so easy as just lengthening telomeres, or else the body would already be doing it! That is to say, no one would fund the study because they thought they knew how it had to come out.
But they were wrong. Even with Cawthon’s small sample of only 143 subjects, the relationship between telomere length and diseases of old age jumped out of the statistics. The quartile with the shortest telomeres had suffered two times higher mortality and three times greater incidence of heart disease in the intervening 20 years than those with the longest telomeres.
Red blood cells have no DNA, hence no telomeres, but white blood cells are constantly dividing to target specific bacterial, so the telomeres in white blood cells are a sensitive measure of immune health. Cawthon reported that the group with shortest telomeres had suffered 9 times the rate of infectious disease compared to the longest telomere group.
Corroborating this finding, In 2015, a Danish study replicated Cawthon’s results on a huge scale. In 60,000 subjects, the study scientists associated short telomeres with all-cause mortality, heart disease, diabetes, and some cancers.
Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality
Peripheral Blood Leukocyte Telomere Length and Mortality Among 64 637 Individuals From the General Population
Line Rode Børge G. Nordestgaard Stig E. Bojesen
JNCI: Journal of the National Cancer Institute, Volume 107, Issue 6, 1 June 2015, djv074, https://doi.org/10.1093/jnci/djv074
Published: 10 April 2015
Thus, at this juncture, there is no question that TS is a senescence factor. It may not be the core factor, but it’s all the more a key factor that we understand the three mechanisms by which TS leads to senescence and high chronic disease risks.
1. First, stem cells with the shortest telomeres stop reproducing, hence the body’s tissues don’t renew as efficiently.
Second, senescent cells are not just dead weight, they actually emit chemical signals (cytokines) that increase inflammation. This has been called SASP, for Senescence-Associated Secretory Phenotype.)
Third, senescence in the bone marrow that generates new white blood cells is especially damaging to the immune system, because it prevents the body from responding effectively when challenged with new infections.
Senes cell elicit repair ? Read that
DOI: 10.1083/jcb.201009094 | Published February 14, 2011
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Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.
Cellular senescence was formally described more than 40 years ago as a process that limited the proliferation (growth) of normal human cells in culture (Hayflick, 1965). This landmark paper contained two