1.  Genomic or genome instability.

Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer and other chronic diseases. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from cellular processes such as transcription and replication that overwhelm high-fidelity DNA repair. Proregia children all share the over-expression of genomic instability. Identifying the causes of genome instability is crucial to understanding genome dynamics during cell proliferation and its role in cancer, aging, and a number of rare genetic diseases.

Genomes are transmitted faithfully from dividing cells to their offspring. Changes that occur during DNA repair, chromosome duplication, and transmission or via recombination provide a natural source of genetic variation. They occur at low frequency because of the intrinsic variable nature of genomes, which we refer to as genome instability. However, genome instability can be enhanced by exposure to external genotoxic agents or as the result of cellular pathologies. (Annu Rev Genet. 2013;47:1-32. Source)

Modern Societies whose lawmakers don’t respect the precautionary principle are rampant with a constant bombardment of genotoxic chemicals from all sides, even at low dose, (Source) including, but not limited to heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length. (Carcinogenesis. 2015 Jun; 36(Suppl 1): S61–S88, Source) The onslaught of these genotoxic substances promotes cancer,  auto-immune diseases and, inter alia, accelerated aging. It is one of the most important causes to this first aging hallmark that we can greatly attenuate.

   2 Mitochondrial DNA Break-down

Mitochondrial function has a profound impact on the aging process. Mitochondrial dysfunction can accelerate aging in mammals (Kujoth et al., 2005; Trifunovic et al., 2004; Vermulst et al., 2008), but it is less clear whether improving mitochondrial function, for example through mitohormesis, can extend lifespan in mammals, although suggestive evidence in this sense already exists.

Mitochondrial Dysfunction

As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus increasing electron leakage and reducing ATP generation (Green et al., 2011) (Figure 4B). The relation between mitochondrial dysfunction and aging has been long suspected but dissecting its details remains as a major challenge for aging research.

As human cells age, the mitochondria start to lose their integrity due to the build-up of free radical damage, inter alia. Degraded mitochondrial function leads to decline in ATP production and an increase in a type of cell death known as apoptosis. This mitochondrial decline is especially noticeable in tissues with high energy demand such as the heart and the brain. This Hallmark is still a strong candidate for being one of Aging’s key engines. (Source. In this contexte, mutations and deletions in aged mtDNA may also contribute to aging (Park and Larsson, 2011). mtDNA has been considered a major target for aging-associated somatic mutations due to the oxidative microenvironment of the mitochondria, the lack of protective histones in the mtDNA, and the limited efficiency of the mtDNA repair mechanisms compared to those of nuclear DNA (Linnane et al., 1989). The causal implication of mtDNA mutations in aging has been controversial because of the multiplicity of mitochondrial genomes, which allows for the co-existence of mutant and wild-type genomes within the same cell, a phenomenon that is referred to as ‘heteroplasmy’. However, single-cell analyses have revealed that, despite the low overall level of mtDNA mutations, the mutational load of individual aging cells becomes significant and may attain a state of homoplasmy in which a mutant genome dominates the normal one (Khrapko et al., 1999). Interestingly, contrary to previous expectations, most mtDNA mutations in adult or aged cells appear to be caused by replication errors early in life, rather than by oxidative damage. These mutations may undergo polyclonal expansion and cause respiratory chain dysfunction in different tissues (Ameur et al., 2011). Studies of accelerated aging in HIV-infected patients treated with anti-retroviral drugs, which interfere with mtDNA replication, have supported the concept of clonal expansion of mtDNA mutations originated early in life (Payne et al., 2011)Overview

There is extensive evidence that genomic damage accompanies aging and that its artificial induction can provoke aspects of accelerated aging. In the case of the machinery that ensures faithful chromosomal segregation, there is genetic evidence that its enhancement can extend longevity in mammals (Baker et al., 2012). Also, in the particular case of progerias associated with nuclear architecture defects, there is proof of principle for treatments that can delay premature aging. Similar avenues should be explored to find interventions that reinforce other aspects of nuclear and mitochondrial genome stability, such as DNA repair, and their impact on normal aging (telomeres constitute a particular case and are discussed separately)

3. Telomere Shortening and Telomerase dormancy is another major aging hallmark.

Telomeres are molecules that are used to determine people’s biological age. The more one’s telomeres are maintained in good shape, in general, the longer he or she can extend lifespan. Telomeres are short sequences of nucleotide repeats found at both ends of each of our 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. The telomerase enzyme synthesizes telomeric DNA and maintains telomere length; in other words, telomerase activity is required to prevent telomere shortening. (Source) Telomerase activity is rarely seen in human somatic cells, but is present in germ cells, stem cells, and in most  human cancer cells. In cancer cells, telomerase expression leads to uncontrolled proliferation.

Studies of exceptionally long-lived animals have provided insights into the relationship between telomeres and longevity. Among mammals, bats live exceptionally long in comparison to their body size. A  study published in Science Advances looked at telomere length and telomerase expression in members of the Myotis genus, which holds the record for longest measured lifespan in wild bats of 41 years. Telomere length does not shorten with age in Myotis bats. However, surprisingly, telomerase was not detected in the blood, which suggests that telomere length is maintained by a different mechanism. Five genes were differentially expressed in the Myotis genus as compared to other mammals, hinting at a novel mechanism for telomere maintenance. Because cancer incidence is practically non existing  in bats, it would be interesting knowing by which mechanism bat telomere stay long.(Source)

Such shortening is typically associated with aging, and 12 of the 17 progeria patients studied — the oldest of whom was 14 — had shortened telomere, similar to what would be found in a healthy 69-year-old. The average person with progeria lives just 13 years, with heart attack and stroke a common cause of death.



Accumulation of DNA damage with age appears to affect the genome near-to-randomly, but there are some chromosomal regions, such as telomeres, that are particularly susceptible to age-related deterioration (Blackburn et al., 2006) (Figure 2A). Replicative DNA polymerases lack the capacity to replicate completely the terminal ends of linear DNA molecules, a function that is proprietary of a specialized DNA polymerase known as telomerase. However, most mammalian somatic cells do not express telomerase and this leads to the progressive and cumulative loss of telomere-protective sequences from chromosome ends. Telomere exhaustion explains the limited proliferative capacity of some types of in vitro cultured cells, the so-called replicative senescence or Hayflick limit (Hayflick and Moorhead, 1961Olovnikov, 1996). Indeed, ectopic expression of telomerase is sufficient to confer immortality to otherwise mortal cells, without causing oncogenic transformation (Bodnar et al., 1998). Importantly, telomere shortening is also observed during normal aging both in human and mice (Blasco, 2007).

Telomeres can be regarded as DNA breaks that are made invisible to the DNA repair machinery through the formation of specialized nucleoprotein complex known as shelterin (Palm and de Lange, 2008). This adds another peculiarity to telomeres, not only telomeres are progressively shortened in the absence of telomerase but, also, even in the presence of telomerase, the infliction of exogenous DNA damage to telomeres becomes invisible to the DNA repair machineries due to the presence of shelterins. Therefore, DNA damage at telomeres causes a persistent type of DNA damage that leads to deleterious cellular effects including senescence and/or apoptosis (Fumagalli et al., 2012Hewitt et al., 2012).

Telomerase deficiency in humans is associated with premature development of diseases, such as pulmonary fibrosis, dyskeratosis congenita and aplastic anemia, which involve the loss of the regenerative capacity of different tissues (Armanios and Blackburn, 2012). Severe telomere uncapping can also result from deficiencies in shelterin components (Palm and de Lange, 2008). Shelterin mutations have been found in some cases of aplastic anemia and dyskeratosis congenita (Savage et al., 2008Walne et al., 2008Zhong et al., 2011). Various loss-of-function models for shelterin components are characterized by rapid decline of the regenerative capacity of tissues and accelerated aging, a phenomenon that occurs even in the presence of telomeres with a normal length (Martinez and Blasco, 2010).

Normal aging is accompanied by telomere attrition in mammals. Moreover, pathological telomere dysfunction accelerates aging in mice and humans, while experimental stimulation of telomerase can delay aging in mice, thus fulfilling all of the criteria for a hallmark of aging.


4. Epigenetic Alterations

A variety of epigenetic alterations affects all cells and tissues throughout life (Talens et al., 2012) (Figure 2B). Epigenetic changes involve alterations in DNA methylation patterns, post-translational modification of histones, and chromatin remodeling. Increased histone H4K16 acetylation, H4K20 trimethylation or H3K4 trimethylation, as well as decreased H3K9 methylation or H3K27 trimethylation, constitute age-associated epigenetic marks (Fraga and Esteller, 2007; Han and Brunet, 2012). The multiple enzymatic systems assuring the generation and maintenance of epigenetic patterns include DNA methyltransferases, histone acetylases, deacetylases, methylases and demethylases, as well as protein complexes implicated in chromatin remodeling.

Histone modifications

Histone methylation meets the criteria for a hallmark of aging in invertebrates. Deletion of components of histone methylation complexes extends longevity in nematodes and flies (Greer et al., 2010; Siebold et al., 2010). Moreover, histone demethylases modulate lifespan by targeting components of key longevity routes such as the insulin/IGF-1 signaling pathway (Jin et al., 2011). It is not clear yet whether manipulations of histone-modifying enzymes can influence aging through purely epigenetic mechanisms, by impinging on DNA repair and genome stability, or through transcriptional alterations affecting metabolic or signaling pathways outside of the nucleus.

DNA methylation

The relationship between DNA methylation and aging is complex. Early studies described an age-associated global hypomethylation, but subsequent analyses revealed that several loci, including those corresponding to various tumor suppressor genes and Polycomb target genes, actually become hypermethylated with age (Maegawa et al., 2010). Cells from patients and mice with progeroid syndromes exhibit DNA methylation patterns and histone modifications that largely recapitulate those found in normal aging (Osorio et al., 2010; Shumaker et al., 2006). All of these epigenetic defects or epimutations accumulated throughout life may specifically affect the behavior and functionality of stem cells (Pollina and Brunet, 2011) (see section on Stem Cell Exhaustion). Nevertheless, thus far there is no direct experimental demonstration that organismal lifespan can be extended by altering patterns of DNA methylation.

Chromatin remodeling

DNA- and histone-modifying enzymes act in concert with key chromosomal proteins, such as the heterochromatin protein 1α (HP1α), and chromatin remodeling factors, such as Polycomb group proteins or the NuRD complex, whose levels are diminished in both normally and pathologically aged cells (Pegoraro et al., 2009; Pollina and Brunet, 2011). Alterations in these epigenetic factors together with the above discussed epigenetic modifications in histones and DNA-methylation determine changes in chromatin architecture, such as global heterochromatin loss and redistribution, which constitute characteristic features of aging (Oberdoerffer and Sinclair, 2007; Tsurumi and Li, 2012). The causal relevance of these chromatin alterations in aging is

Transcriptional alterations

Aging is associated with an increase in transcriptional noise (Bahar et al., 2006), and an aberrant production and maturation of many mRNAs (Harries et al., 2011; Nicholas et al., 2010). Microarray-based comparisons of young and old tissues from several species have identified age-related transcriptional changes in genes encoding key components of inflammatory, mitochondrial and lysosomal degradation pathways (de Magalhaes et al., 2009). These aging-associated transcriptional signatures also affect non-coding RNAs, including a class of miRNAs (gero-miRs) that is associated with the aging process and influences lifespan by targeting components of longevity networks or by regulating stem cell behavior (Boulias and Horvitz, 2012; Toledano et al., 2012; Ugalde et al., 2011). Gain- and loss-of-function studies have confirmed the capacity of several miRNAs to modulate longevity in Drosophila melanogaster and C. elegans (Liu et al., 2012; Shen et al., 2012; Smith-Vikos and Slack, 2012).

Reversion of epigenetic changes

Unlike DNA mutations, epigenetic alterations are – at least theoretically – reversible, hence offering opportunities for the design of novel anti-aging treatments (Freije and Lopez-Otin, 2012; Rando and Chang, 2012). Restoration of physiological H4 acetylation through administration of histone deacetylase inhibitors, avoids the manifestation of age-associated memory impairment in mice (Peleg et al., 2010), indicating that reversion of epigenetic changes may have neuroprotective effects. Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotype and extend longevity of progeroid mice (Krishnan et al., 2011). Moreover, the recent discovery of transgenerational epigenetic inheritance of longevity in C. elegans suggests that manipulation of specific chromatin modifications in parents can induce an epigenetic memory of longevity in their descendants (Greer et al., 2011). Conceptually similar to histone acetyltransferase inhibitors, histone deacetylase activators may conceivably promote longevity. Resveratrol has been extensively studied in relation to aging and among its multiple mechanisms of action is the upregulation of SIRT1 activity, but also other effects associated with energetic deficits (see Mitochondrial Dysfunction).


There are multiple lines of evidence suggesting that aging is accompanied by epigenetic changes, and that epigenetic perturbations can provoke 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.

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5. Loss of Proteostasis

Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis (Powers et al., 2009) (Figure 3). 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). Moreover, there are regulators of age-related proteotoxicity, such as MOAG-4, that act through an alternative pathway distinct from molecular chaperones and proteases (van Ham et al., 2010). All these systems function in a coordinated fashion to restore the structure of misfolded polypeptides or to remove and degrade them completely, thus preventing the accumulation of damaged components and assuring the continuous renewal of intracellular proteins. Accordingly, many studies have demonstrated that proteostasis is altered with aging (Koga et al., 2011). Additionally, chronic expression of unfolded, misfolded or aggregated proteins contributes to the development of some age-related pathologies, such as Alzheimer’s disease, Parkinson’s disease and cataracts (Powers et al., 2009).

Proteolytic systems

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.


There is evidence that aging is associated with perturbed proteostasis, and experimental perturbation of proteostasis can precipitate age-associated pathologies. There are also promising examples of genetic manipulations that improve proteostasis and delay aging in mammals (Zhang and Cuervo, 2008).

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6. Deregulated Nutrient-sensing

The somatotrophic axis in mammals comprises the growth hormone (GH), produced by the anterior pituitary, and its secondary mediator, the insulin-like growth factor (IGF-1), produced in response to GH by many cell types, most notably hepatocytes. The intracellular signaling pathway of IGF-1 is the same as that elicited by insulin, which informs cells of the presence of glucose. For this reason, IGF-1 and insulin signaling are known as the ‘insulin and IGF-1 signaling’ (IIS) pathway. Remarkably, the IIS pathway is the most conserved aging-controlling pathway in evolution and among its multiple targets are the FOXO

The insulin and IGF-1 signaling pathway

Multiple genetic manipulations that attenuate signaling intensity at different levels of the IIS pathway consistently extend the lifespan of worms, flies and mice (Fontana et al., 2010). Genetic analyses indicate that this pathway mediates part of the beneficial effects of DR on longevity in worms and flies (Fontana et al., 2010). Among the downstream effectors of the IIS pathway, the most relevant one for longevity in worms and flies is the transcription factor FOXO (Kenyon et al., 1993; Slack et al., 2011). In mice, there are four FOXO members, but the effect of their over-expression on longevity and their role in mediating increased healthspan through reduced IIS have not yet been determined. Mouse FOXO1 is required for the tumor suppressive effect of DR (Yamaza et al., 2010), but it is not

Other nutrient-sensing systems: mTOR, AMPK and sirtuins

In addition to the IIS pathway that participates in glucose-sensing, three additional related and interconnected nutrient-sensing systems are the focus of intense investigation: mTOR, for the sensing of high amino acid concentrations; AMPK, which senses low energy states by detecting high AMP levels; and sirtuins


Collectively, current available evidence strongly 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).

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Mitochondrial Dysfunction

As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus increasing electron leakage and reducing ATP generation (Green et al., 2011) (Figure 4B). The relation between mitochondrial dysfunction and aging has been long suspected but dissecting its details remains as a major challenge for aging research.

Reactive oxygen species (ROS)

The mitochondrial free radical theory of aging proposes that the progressive mitochondrial dysfunction that occurs with aging results in increased production of reactive oxygen species (ROS), which in turn causes further mitochondrial deterioration and global cellular damage (Harman, 1965). Multiple data support a role for ROS in aging, but we focus here on the developments of the

Mitochondrial integrity and biogenesis

Dysfunctional mitochondria can contribute to aging independently of ROS, as exemplified by studies with mice deficient in DNA polymerase γ (Edgar et al., 2009; Hiona et al., 2010) (see above Genomic Instability). This could happen through a number of mechanisms, for example, mitochondrial


Mitochondrial dysfunctions during aging are also connected with hormesis, a concept on which a number of aging research lines have recently converged (Calabrese et al., 2011). According to this concept, mild toxic treatments trigger beneficial compensatory responses that surpass the repair of the triggering damage, and actually produce an improvement in cellular fitness when compared to the starting pre-damage conditions. Thus, although severe mitochondrial dysfunction is pathogenic, mild respiratory deficiencies may increase lifespan, perhaps due to a hormetic response (Haigis and Yankner, 2010). Such hormetic reactions may consist in the induction of a mitochondrial stress response either in the same tissue in which mi


Mitochondrial function has a profound impact on the aging process. Mitochondrial dysfunction can accelerate aging in mammals (Kujoth et al., 2005; Trifunovic et al., 2004; Vermulst et al., 2008), but it is less clear whether improving mitochondrial function, for example through mitohormesis, can extend lifespan in mammals, although suggestive evidence in this sense already exists.

Mitochondrial Dysfunction

As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus increasing electron leakage and reducing ATP generation (Green et al., 2011) (Figure 4B). The relation between mitochondrial dysfunction and aging has been long suspected but dissecting its details remains as a major challenge for aging research.

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7. Cellular Senescence

Cellular senescence can be defined as a stable arrest of the cell cycle coupled to stereotyped phenotypic changes (Campisi and d’Adda di Fagagna, 2007; Collado et al., 2007; Kuilman et al., 2010) (Figure 5A). 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). The accumulation of senescent cells in aged tissues has been often inferred using surrogate markers such as DNA damage. Some studies have directly used senescence-associated β-galactosidase (SABG) to identify senescence in tissues (Dimri et al., 1995). Of note, a detailed and parallel quantification of SABG and DNA damage in liver produced comparable quantitative data, yielding a total of

The INK4a/ARF locus and p53

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). The number of mechanisms that implement senescence in response to this variety of oncogenic insults has also grown, but, still, the originally reported p16INK4a/Rb and p19ARF/p53 pathways remain, in general, the most important ones (Serrano et al., 1997). The relevance of these pathways for aging becomes even more striking when considering


We propose that cellular senescence is a beneficial compensatory response to damage that becomes deleterious and accelerates aging when tissues exhaust their regenerative capacity. Given these complexities, it is not possible to give a simple answer to the question of whether cell senescence fulfills the third ideal criteria for the definition of a hallmark. A moderate enhancement of the senescence-inducing tumor suppressor pathways may extend longevity (Matheu et al., 2009; Matheu et al., 2007), and, at the same time, elimination of senescent cells in an experimental progeria model delays age-related pathologies (Baker et al., 2011). Therefore, two interventions that are conceptually opposite are able to extend healthspan.

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8. Stem Cell Exhaustion

The decline in the regenerative potential of tissues is one of the most obvious characteristics of aging (Figure 5B). 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). In fact, old INK4a−/− HSCs exhibit b


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. Recent promising studies suggest that stem cell rejuvenation may reverse the aging phenotype at the organismal level (Rando and Chang, 2012).

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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) (Figure 5C). Thus, neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) tends to be deregulated in aging as inflammatory reactions increase, immunosurveillance against pathogens and premalignant cells declines, and the composition of the peri- and 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).

Other types of intercellular communication

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). Conversely, lifespan-extending manipulations targeting one single tissue can retard the aging process in other tissues (Durieux et al., 2011; Lavasani et al., 2012; Tomas-Loba et al., 2008).

Restoring defective intercellular communication

There are several possibilities for restoring defective intercellular communication underlying aging processes, including genetic, nutritional or pharmacological interventions that may improve the cell-cell communication properties that are lost with aging (Freije and Lopez-Otin, 2012; Rando and Chang, 2012). Of special interest in this regard are the DR approaches to extend healthy lifespan (Piper et al., 2011; Sanchez-Roman et al., 2012), and the rejuvenation strategies based on the use of blood-borne systemic factors identified in parabiosis experiments (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011). Moreover, the long-term administration of anti-inflammatory agents such as aspirin may increase longevity in mice and healthy aging in humans (Rothwell et al., 2011; Strong et al., 2008). Additionally, given that the gut microbiome shapes the function of the host immune system and exerts systemic metabolic effects, it appears possible to extend lifespan by manipulating the composition and functionality of the complex and dynamic intestinal bacterial ecosystem of the human body (Claesson et al., 2012; Ottaviani et al., 2011).


There is compelling evidence that aging is not an exclusively cell biological phenomenon and that it is coupled to a general alteration in intercellular communication, offering opportunities to modulate aging at this level. Excitingly, proof of principle exists for rejuvenation through blood-borne systemic factors (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).

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Conclusions and Perspectives

A global view at the nine candidate hallmarks of aging enumerated in this review allows grouping them into three categories: primary hallmarks, antagonistic hallmarks, and integrative hallmarks (Figure 6). The common characteristic of the primary hallmarks is the fact that they are all unequivocally negative. This is the case of DNA damage, including chromosomal aneuploidies, mitochondrial DNA mutations and telomere loss, epigenetic drift, and defective proteostasis. In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity. At low levels, they mediate beneficial effects, but at high levels, they become deleterious. This is the case for senescence, which protects the organism from cancer, but in excess can promote aging; similarly, reactive oxygen species (ROS) mediate cell signaling and survival, but at chronic high levels can produce cellular damage; likewise, an optimal nutrient-sensing and anabolism is obviously important for survival but in excess and during time can become pathological. These hallmarks can be viewed as designed for protecting the organism from damage or from nutrient scarcity, but when exacerbated or chronic, subvert their purpose and generate further damage. A third category comprises the integrative hallmarks, stem cell exhaustion and altered intercellular communication, which directly affect tissue homeostasis and function. Notwithstanding the interconnectedness between all hallmarks, we propose some degree of hierarchical relation between them (Figure 6). The primary hallmarks could be the initiating triggers whose damaging events progressively accumulate with time. The antagonistic hallmarks, being in principle beneficial, become progressively negative in a process that is partly promoted or accelerated by the primary hallmarks. Finally, the integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms. Because the hallmarks co-occur during aging and are interconnected, understanding their exact causal network is an exciting challenge for future work.

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•altered intercellular communication, which is the progressive loss of the cells’ capacity to send important signals to each other and to the organelles that compose them,

••epigenetic alterations, which is a change in the regulation of gene expression, sometimes triggering the decrease (or increase) of the expression of a given protein,

•loss of proteostasis, which is the loss of proper folding for synthesized molecules. It can bring up a functional problematic, since the 3D structure of proteins is fundamental to their function,

•deregulated nutrient sensing, through the deregulation of the signaling pathway for insulin and mTOR,

•cellular senescence, which is when some cells’ activity is put on hold as a response to cellular damage, a protection mechanism the inactivates too many cells as the body ages,

•stem cell exhaustion, which lowers our regeneration capacity.


The  9 Classical Aging Hallmarks on which Holistic medicine has a favorable impact

Second:  The Free Radicals & Oxidative Stress hallmark: Age-related degeneration diseases and aging are also believed to be the result of oxidative stress (ROS activity) and free radical erosion. Exposure to ROS, created through normal cellular metabolism and environmental hazards and inflammation, results in damage to cellular structures, leading to loss of critical cell functions. (Source)

Third:Fourth: Another central hallmark of aging is the epigenetic drift and its Epigenetic Clock. This biochemical phenomenon is characterized by gains and losses in DNA methylation in the genome over time. Experimentation showed that the epigenetic drift occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans. This is one reason why certain animals live for shorter or longer periods of time. Methylation patterns drift steadily throughout life, with methylation increasing in some areas of the genome, and decreasing in others. As we will see via Power Point, these epigenetic changes have linked to the aging process. As for Epigenetics, (without the drift), this discipline deals with the epigenome, meaning “that which is above” the genome. The epigenome appears to be the master program which controls our genetic code by switching off and on genes and their proteins. More later. Next we have  Proteostasis Disorder

Fifth: The decline in the protein quality of our cells, called the loss of proteostasis, is a fundamental mechanism of aging. Our bodies have defenses against cellular stress. However, 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.

Sixth: The Clogging-up and Dysfunctions of the Body’s Six Key Metabolic Detoxification Pathways comes next. There are 6 Phase II detoxification pathways in the body that need to be in good shape for Life to durably withstand the passage of time.  Each conjugation pathway serves a specific purpose of detoxifying certain toxins and toxicants. These biochemical pathways require specific nutrients to function without which humans age faster. Next we have the mTOR pathway. For the anti-aging community, this is a biggy. Next,

Seventh: Autophagy Decline. Autophagy is an evolutionally conserved cytoplasmic degradation system in which varieties of materials are sequestered by a double membrane structure, autophagosome, and delivered to the lysosomes for the degradation. Due to the wide varieties of targets, autophagic activity is essential for cellular homeostasis. Recent genetic evidence indicates that autophagy has a crucial role in the regulation of mammalian lifespan.

Eighth: Lysosome Degradation Lysosomes were discovered more than 60 years ago as highly acidic cellular organelles containing many enzymes responsible for breaking down macromolecules. Since then, their roles have expanded. Today, they are understood as being “…. the main catabolic organelles of a cell and play a pivotal role in a plethora of cellular processes, including responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation. In line with this pleiotropic importance for cellular and organismal life and death, lysosomal dysfunction is associated with many age-related pathologies like Parkinson’s and Alzheimer’s disease, as well as with a decline in lifespan. Conversely, targeting lysosomal functional capacity is emerging as a means to promote longevity” (Source) In addition to these processes, it is interesting to note that lysosomes function in autophagy, the process that breaks down cellular components to allow cell survival and homeostasis in the face of starvation. However, not all byproducts of metabolism can be easily broken down by these catabolic enzymes. As a consequence, in long-lived cell populations lysosomes become bloated & dysfunctional, filled with a mix of hardy waste products called lipofusin. As a consequence, these lysosomes are thus much less able to perform their recycling activities. This contributes to the progression of aging. (2)

Ninth: Nutrient and  Caloric Sensors Dysfunction comes next.  With “wear and tear” and the passage of time, metabolic changes lead to deregulated nutrient sensing. While mammals have multiple nutrient sensing pathways to make sure that our bodies take in just the right amount of nutrients, inter alia, there are three main nutrient sensors that can be optimized for healthy lifespans. These are mTOR, AMPK and insulin, each of which modulate significant biochemical pathways. Most of these sensors affect multiple pathways. Blocking or inhibiting mTOR  for example improves protein handling, increases autophagy and enhances stem cell function. (Source)

Eleventh: 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. (Source)

Twelveth: Stem Cell Depletion As we oxidize (lose electrons), inter alia, 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 with synthetic chemicals and high tech technology. However, most times, this leads to both drug resistance and significant complications and toxic effects. On the other hand, 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 replenishing stem cells for quality living way over 100 years. (Source)

Thirteenth: Tissue Repair Deficiencies Besides Stem cell repair and DNA enzyme-based “cut & paste” repair, there are other tissue and cellular repair mechanisms that go awry with the accumulation les toxicants, oxidative stress and biological entropy, what conventional scientists call aging.  Section under construction.

Fourtheenth: Inter-cellular Communication Haywiring The Altered Inter-cellular Communication. As mammaliam cells divide and transform into senescent cells, their communication with other cells becomes dysfunctional leading to an increase in chronic inflammatory distress signals and misfiring of hormonal and neurotransmitter messaging. As a consequence thereto, hormonal instructions go haywire. For example, the aging hypothalamus changes neurohormone signals, which in turn affects food intake and metabolism. Since the hypothalamus also regulates sleep cycles, these changes can perturb sleep, inhibit DNA repair and, inter alia, accelerating aging even further. (“inter alia” is legal  latin for “among other elements”).

Fiftheenth: Circadian Rythms Disorder The hallmark relative to the circadian pathway is relatively new. The 2017 Nobel Prize in Physiology (Medicine) went to scientists who dug deep to unravel some of the mysteries of circadian biology. When humans don’t respect Nature’s rhythms like the sleep-wake (melatonin-cortisol) cycle, aging is accelerated.

Sixteenth: Microbiota Dysbiosis  The Microbiota’s and the Microbiome’s networking. As we will see, the very same bacteria who have been so essential in the complexification of Life over the last 65 millions of years are living in our guts churning away to make us either sick and short lived or healthy and long lived. For example, supercentenarians have a diversed amount of youthful bacteria whereas sick people who die young have lots of dysbiosis. Microbiome science has been one of the most recent scientific revolutions in Medicine, disproving a big chunk of mainstream medical dogmas. Today, to the bacteria-laden microbiome, micro-biologists have identified inter-related networks of viruses, archeae, fungi, yeast and parasites that all contribute one way or another to the process of human biology, chronic diseases and aging.

17. The Endocannabinoid System’s Under-activation The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. (Source) The endocannabinoid system is also involved in regulating a variety of physiological and cognitive processes including but not limited to general homeostasis and fertility, pregnancy, postnatal development, appetite, pain-sensation, mood, memory, neurogenesis, inflammation, the immune system and, among other biological systems,  the longevity pathways, including, but not limited to brain rejuvenation (neurogenesis),  significant Lou Gehrig’s Disease life extension and general longevity via the dietary restriction signaling pathway. This biological ECS system is at the heart of evolutionary biology, ontological experience and optimal longevity. It is so important that scientists have created a new deficiency disease called “Clinical Cannabinoid Deficiency” disorder(Source)

While the body is able to activate the ECS’s endocannibinoid receptors on its own, given mainstream’s toxicity, stress and conventional synthetic drug and trauma based medicine, much of the human and mamalian endocannabinoid system is under-activated or inhibited. Hence, the lack of wellbeing and joie de vivre. (Source). A holistic lifestyle with certain cannabinoid plants can partially remedy this deficiency, thanks to which a healthy lifespan can be better assured.  Helichrysum, Echinacea, (containing cannabinoids called N-alkylamides),  liverwortblack pepper and a few others plants that contain cannabinoids can help, but cannabis is by far the most abundant and rich in healthy and longevity producing cannabinoids, over 80 of them, all integrated within the “whole” in the right proportions. (Source)

To significantly extend healthy human lifespans, we should therefore better reintegrate cannabinoid plants in mainstream’s Pharmacies and educate Health professionals and patients to include this plant in their practice, meals and gardens, from euthanasia, helichrysum and black pepper and to cannabis and more. Education should also examine how to use cannabinoids’ medicinal properties so as to avoid side effects and mis-use. Additional government-funded research on cannabis’ impact on healthy lifespan would also be useful. (The Government’s “public health” authorities have only allowed to grant research on whatever may be toxic with cannabis)..

 18: Thymus Dysfunction

Last, we have the thymus. An underestimated organ, the thymus is key in immune function. Because it shrinks with age, mainstream medical scientists have written off its importance. But this super-gland that inhabits our chest may be one of the most over-looked and important that need not shrink when holistic conditions prevail.

Section under construction

Klotho proteins are expressed predominantly in the kidneys, but also in various tissues and organs including adipose (fat) tissue, the brain, liver, pancreas, bladder, skeletal muscle, and the thyroid gland. Studies have shown that Klotho serum levels decrease with age in humans, indicating the role of the protein in aging. Klotho proteins plays a significant role in regulating metabolic functions that lead to age-related diseases. Importantly, they protect cells and tissues from oxidative stress. Klotho deficiency is implicated in a number of diseases including chronic kidney diseasecancerhypertensionskin atrophy, and diabetes. Klotho gene polymorphisms are associated with osteoporosis, a condition in which bones become weak and brittle, and spondylosis, an age-related degeneration of the spine.

Several studies have shown promising results in the use of Klotho proteins as therapeutic agents to help in slowing down the progression of kidney diseasesdiabetes, and cancer.

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). But for the Happiness Medicine Institute’s executive Committee, the central cause is this constant onslaught of low and not so low bombardment of chemicals, fake food and chronic stress the American government still refuses to properly regulate as well as the refusal of those who control the Government to promote a holistic culture based on sustainability, holistic medicine and, inter alia, an UBI policy. If these two conditions were respected, then most people would avoid chronic diseases, at which point the red carpet of 120 years would unfold.

Sirtuins and aging:

Sirtuins are important proteins for stress resistance and mitochondrial regulation. The Sir genes that encodes sirtuins were first identified in yeast as a regulator of lifespan. In mammals, there are seven sirtuin family members. Researchers have found an interesting link between dietary restrictions, such as fasting, and longevity. Some studies have shown that restricted diet plans and episodic fasting activate mitochondrial sirtuins and slow down aging. The proposed mechanism of action relates to NAD+, which sirtuins require to function. Fasting induces oxidation of NADH to NAD+, and resulting high NAD+ levels activate mitochondrial sirtuins, thus suppressing the formation of reactive oxygen species, which could ultimately lead to reduced aging.

 Complementary Variables

ATP (glucose-ketones-acetate), Redox (electron donors and takers), Ph and Longevity Genes, including but not limited to the Sirtuin Genes

ATP dysfunctioning is also an issue. The way our mitochondria burn fuel via the ATP system (i.e., most of the ATP that is produced by aerobic cellular respiration is made by oxidative phosphorylation) is one of the keys to aging. While much attention has been focused on the fat burnig fuel called keto-diet, the biochemical reality is that keto-dieting is deleterious long term for the human health. While essential fats are vital, the human body makes most of what it needs with a plant-strong diet. A Mediterranean diet can also be beneficial. On the other hand, while there may be some short term benefits with ketogenic diets, minimizing quality carb fueling as well lactate burning and focusing on animal fats are dietary mistake from the viewpoint of healthy lifespans and science. To these questions will be added an analysis of Redox, PH and longevity & DNA repair genes, including the Sirtuin Family.

FOr conc

Located at the end of our chromosomes, these DNA repeats modulate the number of times cells divide. The longer the telomeres, the more cells divide, from 50 divisions or doublings to 70 for example, which corresponds to about 120 years, which has been called the Hayflick limit. The shorter telomeres get, the less they divide. When they can no longer divide, then go into senescence mode, and that not only clogs up the system, but accelerated aging.

Happiness Medicine & Holistic Medicine Posts



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