The Hallmarks of Aging

In the paper

“Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotype and extend longevity of progeroid mice (Krishnan et al., 2011).”

What the sources say

• Disputed

  The paper's Discussion reports that histone deacetylase (HDAC) inhibition—not histone acetyltransferase inhibition—mitigated progeroid phenotypes and extended the lifespan of Zmpste24-deficient mice. It also reports that increasing acetyltransferase Mof activity rescued early senescence in cultured cells, contrary to the claimed direction of intervention. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  cites Krishnan et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“In addition to these direct lesions in the DNA, defects in the nuclear architecture, known as laminopathies, can cause genome instability and result in premature aging syndromes (Worman, 2012).”

What the sources say

• Partly supported

  The Pathophysiology and potential treatments section (page not provided) links lamin abnormalities to premature-aging syndromes and reports a correlation between progerin accumulation, defective DNA repair, and genomic instability. It says the downstream effects of altered nuclear morphology are less established and that abnormal morphology itself does not appear to be the direct cause of tissue dysfunction. The claim therefore overstates the evidence that defects in nuclear architecture cause genomic instability and the syndromes. (LLM, conf=0.85)

  cites Worman, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Maegawa et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“In particular, transgenic overexpression of mammalian SIRT1, which is the closest homologue to invertebrate Sir2, improves aspects of health during aging but does not increase longevity (Herranz et al., 2010).”

What the sources say

• Supported

  The Discussion states that approximately threefold Sirt1 upregulation improved healthy aging but not longevity in mice under standard feeding conditions. The Results report improved age-related glucose tolerance and bone density, while survival did not differ from wild-type controls. (LLM, conf=0.94)

  cites Herranz et al., 2010 source

In the paper

“The causal relevance of these chromatin alterations in aging is supported by the finding that flies with loss-of-function mutations in HP1α have a shortened lifespan, whereas overexpression of this heterochromatin protein extends longevity in flies and delays the muscular deterioration characteristic of old age (Larson et al., 2012).”

What the sources say

• Supported

  In Results/Discussion (‘Heterochromatin levels are important for longevity’), the paper reports that flies heterozygous for an HP1 loss-of-function allele lived shorter lives, while flies overexpressing HP1 lived longer than controls. The muscle-integrity section reports that HP1-overexpressing flies maintained intestinal muscle integrity beyond 40 days, whereas wild-type flies showed progressive age-related degeneration. (LLM, conf=0.93)

  cites Larson et al., 2012 source

In the paper

“Thus, mice with shortened or lengthened telomeres exhibit decreased or increased lifespan, respectively (Armanios et al., 2009; Rudolph et al., 1999; Tomas-Loba et al., 2008).”

What the sources say

• Partly supported

  The Results (page not provided) report progressively worse survival in successive generations of telomerase-deficient mice with short telomeres. The paper does not show that lengthened telomeres increase lifespan; it also says the observed premature deaths in short-telomere mice with wild-type telomerase were not statistically significant. (LLM, conf=0.88)

  cites Armanios et al., 2009 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Rudolph et al., 1999 source
• ?Not checked — no full text of the sourcecites Tomas-Loba et al., 2008 source

In the paper

“In particular, heterochromatin assembly at pericentric regions requires trimethylation of histones H3K9 and H4K20, as well as HP1α binding, and is important for chromosomal stability (Schotta et al., 2004).”

What the sources say

• Partly supported

  The sections on pericentric heterochromatin and HP1 interactions report enrichment of both trimethylation marks and propose a sequential pathway involving HP1α and HP1β. The paper calls that assembly pathway a tentative model, rather than demonstrating that all three components are required. In “Suv4-20h enzymes are novel Su(var) genes” (page unavailable), it identifies protection of genome stability as a function of heterochromatin, while describing H4-K20 trimethylation’s participation as a prediction. (LLM, conf=0.86)

  cites Schotta et al., 2004 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Fraga and Esteller, 2007 source
• Partly supported

  The section ‘Other methylation marks in worm, fly and mammalian longevity’ reports increased H4K20me3 with age in rat livers and reduced H3K9me3 in cells from patients with a premature-aging syndrome; the H3K27me3 section reports a decrease with age in worms (page numbers unavailable). But the paper reports an age-dependent loss of H3K4me3 in flies and fewer H3K4me3-marked loci in older human neurons, rather than the claimed general increase. The passages found do not establish an age-related increase in H4K16 acetylation. (LLM, conf=0.87)

  cites Han and Brunet, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports that some cardiomyocytes from centenarian donors had substantial deletion loads, despite most cells having none. But the largest fraction reported was one-third of mitochondrial genomes in a cell; the study does not show a mutant genome dominating the normal one or reaching homoplasmy. (LLM, conf=0.90)

  cites Khrapko et al., 1999 sourceExperimental — accuracy not yet measured

In the paper

“In addition to these age-associated changes in A-type lamins, lamin B1 levels decline during cell senescence, pointing to its utility as a biomarker of this process (Freund et al., 2012; Shimi et al., 2011).”

What the sources say

• Supported

  The Introduction states that lamin B1 declines when human and mouse cells undergo senescence and calls its loss an easily detectable biomarker of the senescent state. The Discussion likewise describes the decline as a hallmark of senescence, while noting a possible exception under oxidative stress. (LLM, conf=0.94)

  cites Freund et al., 2012 source
• Supported

  In “Changes in the expression of LB1 during senescence” (page not provided), lamin B1 protein fell by approximately 80%–90% as WI-38 cells became senescent, while lamin levels remained unchanged in quiescent cells. This association supports the hedged suggestion that declining lamin B1 could be useful as a senescence biomarker; the paper does not establish it as a validated diagnostic test. (LLM, conf=0.90)

  cites Shimi et al., 2011 source

In the paper

“These pathways include the activation of p53 (Varela et al., 2005), deregulation of the somatotrophic axis (Marino et al., 2010), and attrition of adult stem cells (Espada et al., 2008; Scaffidi and Misteli, 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Varela et al., 2005 source
• Supported

  Marino et al. is cited for deregulation of the somatotroph axis, not for p53 activation or stem-cell attrition. The Results report altered somatotroph-axis signaling in progeroid mice, note a similar pattern reported in some people with HGPS, and suggest that a change also seen in HGPS cells contributes to axis suppression. (LLM, conf=0.90)

  cites Marino et al., 2010 source
• Partly supported

  The Results and discussion report impaired proliferative capacity of adult epidermal stem cells in Zmpste24-deficient mice, supporting stem-cell dysfunction linked to nuclear-envelope defects. But the same section reports an increase—not attrition—in stem-cell markers in the hair-follicle bulge. This citation is attached only to the adult-stem-cell part of the sentence, not the p53 or somatotrophic-axis claims. (LLM, conf=0.87)

  cites Espada et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“Cells from these mice show impaired mitochondrial function but, unexpectedly, this is not accompanied by increased ROS production (Edgar et al., 2009; Hiona et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Edgar et al., 2009 source
• Partly supported

  The Results (‘Mitochondrial bioenergetics is impaired in D257A mice’; page unavailable) report reduced respiration in skeletal-muscle mitochondria. The Results (‘Skeletal muscle mitochondria from D257A mice produce significantly fewer ROS’; page unavailable) report decreased H2O2 production, supporting the absence of increased ROS. The paper’s measurements are of skeletal-muscle mitochondria, however, not cells from these mice generally. (LLM, conf=0.84)

  cites Hiona et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, transgenic mice overexpressing BubR1, a mitotic checkpoint component that ensures accurate segregation of chromosomes, exhibit an increased protection against aneuploidy and cancer, and extended healthy lifespan (Baker et al., 2012).”

What the sources say

• Supported

  The Abstract reports that transgenic mice with sustained high BubR1 expression had reduced aneuploidy and tumorigenesis, extended lifespan, and delayed age-related deterioration in several tissues. It also identifies BubR1 as a mitotic regulator involved in accurate chromosome segregation. (LLM, conf=0.94)

  cites Baker et al., 2012 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Boulias and Horvitz, 2012 source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Toledano et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  In “The Growing Relevance of miRNAs in Aging,” the paper reports age-related changes in miRNA expression and lifespan effects through aging-related pathways in C. elegans. “GeromiRs, a New and Expanding Group of miRNAs” also describes miRNAs regulating stem-cell behavior, but does not establish that this regulation changes lifespan; it says miRNAs’ contribution to aging still requires further study. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites Ugalde et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Freije and Lopez-Otin, 2012 source
• Supported

  In “Aging and Epigenetics” (page not specified), the paper contrasts potentially reversible manifestations of aging with mutated or deleted DNA sequences that are inaccessible to rejuvenation. Its “Concluding Remarks” propose that rejuvenating interventions modify the epigenome, and “Rejuvenation: Is It Epigenetic Reprogramming?” discusses therapeutic applications. Together, these support the claim’s theoretical framing. (LLM, conf=0.90)

  cites Rando and Chang, 2012 source

In the paper

“and subsequent reports indicated that enhanced expression of the worm (sir-2.1) and fly (dSir2) orthologs could extend lifespan in both invertebrate model systems (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001).”

What the sources say

• Supported

  The Results report that increased dSir2 expression extended lifespan in flies, the part of the sentence attributed to Rogina and Helfand (2004). The worm finding has a separate citation and is not needed to assess this source. (LLM, conf=0.93)

  cites Rogina and Helfand, 2004 source
• ?Not checked — no full text of the sourcecites Tissenbaum and Guarente, 2001 source

In the paper

“Alterations of the nuclear lamina and production of an aberrant prelamin A isoform called progerin have also been detected during normal human aging (Ragnauth et al., 2010; Scaffidi and Misteli, 2006).”

What the sources say

• Supported

  The Clinical Perspective (p. 2210) reports progerin production in cells from both young and old individuals and its accumulation in a small fraction of skin fibroblasts from aged individuals. The paper also reports nuclear morphology defects in aged vascular smooth muscle cells, although its own experiments found prelamin A accumulation rather than progerin in those cells. (LLM, conf=0.88)

  cites Ragnauth et al., 2010 source
• Supported

  The results accompanying Fig. 3 report Δ50 lamin A in healthy cells and tissue from old individuals, alongside altered lamin A/C localization in cells from old donors. The discussion identifies Δ50 lamin A as an aberrant, uncleaved pre-lamin A isoform produced in healthy individuals. The paper uses “Δ50 lamin A” rather than “progerin.” (LLM, conf=0.91)

  cites Scaffidi and Misteli, 2006 source

In the paper

“The causal relevance of nuclear lamina abnormalities in premature aging has been supported by the observation that decreasing prelamin A or progerin levels delays the onset of progeroid features and extends lifespan in mouse models of HGPS.”

What the sources say

• Partly supported

  The treatment results (p. 5, Fig. 4D) report that morpholinos reduced progerin, improved body weight and lordokyphosis, and extended survival in HGPS-model mice. They show amelioration of progeroid features, but do not establish that the onset of those features was delayed. (LLM, conf=0.84)

  cites Osorio et al., 2011 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Varela et al., 2008 source
• Partly supported

  The Results (page unavailable) show that mice with one progerin-producing allele developed features later and survived longer than mice with two; FTI treatment also improved several disease features. But the paper does not show that experimentally decreasing prelamin A or progerin protein levels delayed onset or extended lifespan, and it does not report a survival benefit from FTI treatment. (LLM, conf=0.84)

  cites Yang et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“GH and IGF-1 levels decline during normal aging, as well as in mouse models of premature aging”

What the sources say

• Partly supported

  The Introduction reports attenuation of the GH/IGF1 axis in naturally aged mice, and the Results report suppression of that axis in progeroid mice. These passages concern signaling and gene expression, not measured GH and IGF-1 hormone levels; the claim is more specific than the evidence. (LLM, conf=0.88)

  cites Schumacher et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“Regarding autophagy, transgenic mice with an extra copy of the chaperone-mediated autophagy receptor LAMP2a do not experience aging-associated decline in autophagic activity and preserve improved hepatic function with aging (Zhang and Cuervo, 2008).”

What the sources say

• Supported

  The paper reports that an exogenous LAMP-2A copy preserved chaperone-mediated autophagy activity in aged mouse liver at levels similar to those in young mice (Abstract, Fig. 1g). It also reports improved liver function in aged transgenic mice on the zoxazolamine assay (Abstract, Fig. 4d). (LLM, conf=0.93)

  cites Zhang and Cuervo, 2008 source

In the paper

“Moreover, activation of the master regulator of the heat-shock response, the transcription factor HSF-1, increases longevity and thermotolerance in nematodes (Chiang et al., 2012; Hsu et al., 2003), while amyloid-binding components can maintain proteostasis during aging and extend lifespan (Alavez et al., 2011).”

What the sources say

• Supported

  The Results report that HSF-1 overexpression significantly extended lifespan in wild-type C. elegans. They also report that reducing DDL-1/2 increased HSF-1 activity and resistance to heat stress, supporting the statement about thermotolerance. The Introduction identifies HSF-1 as a regulator of the heat-shock response. (LLM, conf=0.86)

  cites Chiang et al., 2012 source
• ?Not checked — no full text of the sourcecites Hsu et al., 2003 source

In the paper

“mTOR activity increases during aging in mouse hypothalamic neurons, contributing to age-related obesity, which is reversed by direct infusion of rapamycin to the hypothalamus”

What the sources say

• Partly supported

  The Introduction reports increased mTOR signaling in hypothalamic POMC neurons of old mice, and the Results report weight loss after intracerebral rapamycin infusion. However, the Results and Materials and Methods specify infusion into the lateral ventricle, not direct infusion into the hypothalamus. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites Yang et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Mice with increased dosage of the tumor suppressor PTEN exhibit a general down-modulation of the IIS pathway and an increased energy expenditure that is associated with improved mitochondrial oxidative metabolism, as well as with an enhanced activity of the brown adipose tissue”

What the sources say

• Partly supported

  The Results sections report repressed PI3K-Akt signaling, higher energy expenditure in Super-PTEN mice, and evidence consistent with increased mitochondrial oxidative metabolism. However, the paper does not report enhanced brown adipose tissue activity; searches for brown adipose tissue and thermogenesis found no supporting passage in our copy. The mitochondrial findings are also partly from cells derived from the mice, rather than direct measurements of mitochondrial metabolism in the mice. (LLM, conf=0.88)

  cites Garcia-Cao et al., 2012 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Ortega-Molina et al., 2012 source

In the paper

“In mice, treatment with rapamycin also extends longevity in what is considered the most robust chemical intervention to increase lifespan in mammals”

What the sources say

• Partly supported

  The supplied passages (labeled Abstract; no page given) report that rapamycin extended median and maximum lifespan in male and female mice at three independent sites. They also describe earlier dietary additives as having weak effects, but do not establish that rapamycin is considered the most robust chemical intervention for increasing lifespan across mammals. (LLM, conf=0.84)

  cites Harrison et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“Collectively, current available evidence strongly supports the idea that anabolic signaling accelerates aging, and decreased nutrient signaling extends longevity”

What the sources say

• Supported

  The Introduction states that many longevity-extending mutations decrease nutrient-signaling activity. The sections on worms and rodents report longer lifespans after reducing TOR, insulin-like, or growth-hormone signaling, supporting the cited sentence’s broad summary of the evidence. (LLM, conf=0.88)

  cites Fontana et al., 2010 source

In the paper

“mTOR, for the sensing of high amino acid concentrations; AMPK, which senses low energy states by detecting high AMP levels; and sirtuins, which sense low energy states by detecting high NAD+ levels”

What the sources say

• Supported

  The Abstract identifies TOR, AMPK, and sirtuins as sensors of changes in amino acids, AMP, and NAD+, respectively. The “Longevity genes and metabolic pathways” section links TOR to nutrient availability and reports that energy stress raises the AMP/ATP ratio and NAD+ levels, activating AMPK and stimulating SIRT1. The claim is a fair paraphrase of these passages. (LLM, conf=0.87)

  cites Houtkooper et al., 2010 source

In the paper

“Other mechanisms causing defective bioenergetics include accumulation of mutations and deletions in mtDNA, oxidation of mitochondrial proteins, destabilization of the macromolecular organization of respiratory chain (super)complexes, changes in the lipid composition of mitochondrial membranes, alterations in mitochondrial dynamics resulting from imbalance of fission and fusion events, and def”

What the sources say

• Partly supported

  The Introduction (page not provided) says ROS can damage mitochondrial proteins, DNA and lipids, and identifies mitophagy as a mitochondrial quality-control process. It does not identify mtDNA mutations or deletions, respiratory-chain supercomplex destabilization, altered membrane-lipid composition, or a fission–fusion imbalance as causes of defective bioenergetics. Its discussion of mitophagy also does not directly establish that defective mitophagy causes defective bioenergetics. (LLM, conf=0.86)

  cites Wang and Klionsky, 2011 sourceExperimental — accuracy not yet measured

In the paper

“Also, mutant mice deficient in a co-chaperone of the heat-shock family exhibit accelerated-aging phenotypes, whereas long-lived mouse strains show a marked up-regulation of some heat-shock proteins (Min et al., 2008; Swindell et al., 2009).”

What the sources say

• Supported

  Min et al. supports the part of the sentence concerning CHIP-deficient mice; the separate claim about long-lived mouse strains is paired with Swindell et al. The Abstract identifies CHIP as an Hsp70-interacting cochaperone and reports accelerated age-related phenotypes in CHIP-deficient mice. The Discussion likewise reports accelerated aging phenotypes in CHIP−/− mice. Page numbers were not supplied. (LLM, conf=0.94)

  cites Min et al., 2008 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Swindell et al., 2009 source

In the paper

“In the cases of resveratrol and the sirtuin activator SRT1720, there is convincing evidence that they protect from metabolic damage and improve mitochondrial respiration in a PGC-1α-dependent fashion”

What the sources say

• Partly supported

  The Abstract reports that resveratrol improved health in mice on a high-calorie diet, increased mitochondrial number, and increased PGC-1α activity. The Discussion likewise lists improved insulin sensitivity, PGC-1α activity, and mitochondrial number. The paper does not report results for SRT1720, demonstrate improved mitochondrial respiration, or establish that the benefits depend on PGC-1α. (LLM, conf=0.90)

  cites Baur et al., 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Feige et al., 2008 source
• Partly supported

  The Introduction and Discussion report that resveratrol increased mitochondrial activity through PGC-1α and protected high-fat-diet mice from obesity and insulin resistance. The paper does not report findings for SRT1720, so it cannot support the claim about both compounds. (LLM, conf=0.88)

  cites Lagouge et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, activation of the master regulator of the heat-shock response, the transcription factor HSF-1, increases longevity and thermotolerance in nematodes (Chiang et al., 2012; Hsu et al., 2003), while amyloid-binding components can maintain proteostasis during aging and extend lifespan (Alavez et al., 2011).”

What the sources say

• Supported

  The paper reports that amyloid-binding compounds improved protein homeostasis and extended lifespan in C. elegans. In the Abstract, it describes Thioflavin T suppressing protein aggregation and extending lifespan, with other amyloid-binding compounds also increasing lifespan. (LLM, conf=0.94)

  cites Alavez et al., 2011 source

In the paper

“Pten-overexpressing mice, as well as hypomorphic PI3K mice show an increased longevity”

What the sources say

• Partly supported

  The Results section reports a modest lifespan extension in male mice with partial p110α PI3K inactivation, but only among those surviving to middle age; it reports no lifespan difference in females. The Discussion describes improved metabolism in PTEN-overexpressing mice but does not state that those mice lived longer. (LLM, conf=0.88)

  cites Foukas et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Ortega-Molina et al., 2012 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hartl et al., 2011 source
• Supported

  Section 2 describes chaperones helping proteins reach a stable folded state and directing proteins that fail to fold toward degradation. Section 3.1 identifies hsp70, hsp60 and hsp90 as the main cytosolic chaperone families and names the proteasome and lysosomes as the two major proteolytic systems linked to them. (LLM, conf=0.91)

  cites Koga et al., 2011 source
• Partly supported

  The Neurodegeneration section describes protein degradation by autophagy alongside the ubiquitin–proteasome system, and Figure 1 describes breakdown of autophagic contents after fusion with a lysosome. The copy does not support the sentence’s separate claim that heat-shock proteins are the most prominent mechanism for stabilizing correctly folded proteins. (LLM, conf=0.88)

  cites Mizushima et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“although severe mitochondrial dysfunction is pathogenic, mild respiratory deficiencies may increase lifespan, perhaps due to a hormetic response”

What the sources say

• Supported

  In “Mitochondrial Function, Oxidative Stress and Aging” (page not provided), the review reports that moderate inhibition of mitochondrial gene expression extended lifespan, whereas high inhibition reduced it. It also says the mechanism may involve a mitochondrial stress response similar to hormesis. (LLM, conf=0.93)

  cites Haigis and Yankner, 2010 source

In the paper

“Genetic down-regulation of mTORC1 activity in yeast, worms and flies extends longevity and attenuates further longevity benefits from DR, suggesting that mTOR inhibition phenocopies DR”

What the sources say

• Partly supported

  The “mTOR and known longevity factors” section reports that genetic changes in the mTORC1 pathway extend lifespan in yeast, worms and flies. Its “Dietary restriction” subsection reports that dietary restriction does not further extend lifespan in the cited yeast experiment and describes a similar result in worms, but it does not establish the same attenuation in flies; it also notes additive benefits in some worm experiments. The claim overgeneralizes a complex, protocol-dependent relationship. (LLM, conf=0.88)

  cites Johnson et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“This mitochondrial decline also occurs during physiological aging in wild-type mice and can be partially reversed by telomerase activation”

What the sources say

• Supported

  The Results section (‘AAV9-mTERT treatment late in life improves metabolic and mitochondrial fitness’) reports a decline in metabolic and mitochondrial markers in two-year-old wild-type control mice compared with one-year-old mice. That decline was less apparent in the telomerase-treated cohorts, supporting the claim of partial reversal. (LLM, conf=0.91)

  cites Bernardes de Jesus et al., 2012 source

In the paper

“In mammalian cells, deacetylation of HSF-1 by SIRT1 potentiates the transactivation of heat-shock genes such as Hsp70, whereas down-regulation of SIRT1 attenuates the heat-shock response (Westerheide et al., 2009).”

What the sources say

• Supported

  The Abstract states that SIRT1 maintains HSF1 in a deacetylated, DNA-binding-competent state at the Hsp70 promoter and that SIRT1 down-regulation accelerates attenuation of the heat-shock response. The reported experiments also show that SIRT1 depletion reduces heat-shock-induced hsp70 mRNA and HSF1 binding to its promoter. (LLM, conf=0.94)

  cites Westerheide et al., 2009 source

In the paper

“Similarly, nutrient supplementation with polyamine preparations containing spermidine or provision of a polyamine-producing gut flora increases longevity in mice (Matsumoto et al., 2011; Soda et al., 2009).”

What the sources say

• Supported

  The Results report that mice given the probiotic LKM512 survived significantly longer than controls and had higher fecal polyamine concentrations. The Discussion links the probiotic treatment to polyamines produced by altered colonic microbiota. Matsumoto et al. thus supports the gut-flora part of the sentence; the dietary-supplementation part is separately cited to Soda et al. (LLM, conf=0.91)

  cites Matsumoto et al., 2011 source
• ?Not checked — no full text of the sourcecites Soda et al., 2009 source

In the paper

“As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus increasing electron leakage and reducing ATP generation”

What the sources say

• Supported

  The Introduction says mitochondrial mutations accumulate and compromise the efficiency of oxidative phosphorylation, which produces ATP. “Damaging mitochondrial signals in inflammation and cell death” says damaged or mutated mitochondria can incompletely reduce more oxygen, generating more superoxide; the paper also describes low mitochondrial ATP production. Together, these passages support the paraphrase. (LLM, conf=0.88)

  cites Green et al., 2011 source

In the paper

“compounds such as metformin and resveratrol are mild mitochondrial poisons that induce a low energy state characterized by increased AMP levels and activation of AMPK”

What the sources say

• Partly supported

  The Discussion (page unavailable) identifies metformin and resveratrol as inhibitors of mitochondrial ATP production that activate AMPK through increased cellular AMP. It does not support calling their effects uniformly mild: it describes metformin as causing “rather severe inhibition” of the respiratory chain in HEK293 cells. (LLM, conf=0.82)

  cites Hawley et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“an increase in FGF2 signaling in the aged muscle stem cell niche results in the loss of quiescence, and eventually in stem cell depletion and diminished regenerative capacity, while suppression of this signaling pathway rescues these defects”

What the sources say

• Partly supported

  The Discussion and Results report that elevated niche-derived FGF signaling causes loss of quiescence, stem-cell depletion, and diminished regenerative capacity. Inhibiting the pathway preserves quiescence and improves stem-cell self-renewal, but the Results also report 30% smaller repaired muscle fibers after FGFR1 inhibition; the claim that suppression rescues diminished regenerative capacity is therefore not supported. (LLM, conf=0.88)

  cites Chakkalakal et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“conditional expression of an NF-κB inhibitor in the aged skin of transgenic mice causes the phenotypic rejuvenation of this tissue, as well as the restoration of the transcriptional signature corresponding to young age”

What the sources say

• Partly supported

  In “Inducible genetic blockade reveals a role for NF-κB in enforcement of aging phenotypes,” the paper reports that blocking NF-κB in aged transgenic mouse skin increased epidermal thickness and proliferation and reduced senescence markers. It also reports a shift toward young-skin gene expression, but only 225 of 414 age-associated genes reached levels indistinguishable from young samples; the authors explicitly call the rejuvenation of whole-skin expression incomplete. No page numbers are provided in our copy. (LLM, conf=0.88)

  cites Adler et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“transplantation of muscle-derived stem cells from young mice to progeroid mice extends lifespan and improves degenerative changes of these animals even in tissues where donor cells are not detected, suggesting that their therapeutic benefit may derive from systemic effects caused by secreted factors”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Lavasani et al., 2012 source

In the paper

“Inflammation is also involved in the pathogenesis of obesity and type 2 diabetes, two conditions that contribute to, and correlate with aging in the human population”

What the sources say

• Partly supported

  In “The metabolic syndrome of aging” (page unavailable), the paper says proinflammatory cytokines interfere with insulin action and links age-related metabolic changes to disease and accelerated aging. “Body composition changes and aging” (page unavailable) links inflammatory markers to insulin resistance and its age-associated conditions. It does not say inflammation contributes to the pathogenesis of obesity; instead, it describes visceral fat as a source of inflammatory cytokines. (LLM, conf=0.85)

  cites Barzilai et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“In the case of senescent tumor cells, there is good evidence that they are subjected to strict immune surveillance and are efficiently removed by phagocytosis”

What the sources say

• Partly supported

  The discussion of established liver carcinomas (p. 3) reports immune clearance of senescent tumor cells by a response involving macrophages, neutrophils, and NK cells. It does not establish phagocytosis as the mechanism of removal, and the evidence described is specific to liver tumors rather than senescent tumor cells generally. (LLM, conf=0.87)

  cites Hoenicke and Zender, 2012 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Kang et al., 2011 source
• Partly supported

  The Abstract reports that innate immune cells participate in clearing senescent murine liver tumours after p53 restoration. It describes phagocytosis as a presumed mechanism alongside direct cytotoxic killing, and explicitly says it is unclear whether senescent-cell turnover is general. The claim overstates both the certainty of phagocytosis and the applicability to senescent tumour cells generally. (LLM, conf=0.87)

  cites Xue et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“These alterations result in an enhanced activation of the NLRP3 inflammasome and other pro-inflammatory pathways, finally leading to increased production of IL-1ß, tumor necrosis factor and interferons”

What the sources say

• Partly supported

  The Introduction says inflammasome activation leads to processing of interleukin-1, and “Damaging mitochondrial signals in inflammation and cell death” links mitochondrial ROS to NLRP3 activation. That section also describes type I interferon production through a separate viral-RNA sensing pathway. The copy does not identify tumor necrosis factor as an outcome or establish that the aging-related alterations increase production of all three mediators. (LLM, conf=0.87)

  cites Green et al., 2011 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and the ‘Inflammasomes’ section (pages not provided) link age-related changes to NLRP3 activation and IL-1β secretion. The ‘Inflammaging’ section reports higher serum TNF-α with aging, but does not establish it as a downstream product of NLRP3 activation. The passages do not support the claimed increase in interferons. (LLM, conf=0.88)

  cites Salminen et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“AUF1-deficient mice exhibit a marked cellular senescence and premature aging phenotype that can be rescued by re-expression of this RNA-binding factor”

What the sources say

• Supported

  The Results section on accelerated aging and cellular senescence reports aging hallmarks and increased senescence staining in Auf1−/− mice. The Results sections on genetic anticipation and telomere erosion report improved survival and restoration of critically short telomeres after AUF1 was reintroduced through breeding, supporting the rescue claim. (LLM, conf=0.89)

  cites Pont et al., 2012 source

In the paper

“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”

What the sources say

• Partly supported

  The Inflammaging section links aging to immunosenescence and NF-κB activation, while the Abstract and “Autophagy declines with aging” section explain how defective autophagy can promote inflammation. The copy does not establish the claimed failure of the immune system to clear pathogens and dysfunctional host cells, or identify cytokine secretion by senescent cells as a cause. Page numbers were not supplied. (LLM, conf=0.85)

  cites Salminen et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“mutant mice with premature aging due to extensive and persistent damage, present dramatic levels of senescence and their progeroid phenotypes are ameliorated by elimination of p16Ink4a or p53”

What the sources say

• Partly supported

  The Results section ('Brca1 Δ11/Δ11 embryos show senescence and senescence-like growth defects'; page not given) reports strong senescence-marker staining, and the paper documents premature aging in Brca1-mutant mice. But the Discussion says that reducing p53 dosage lets embryos bypass senescence without preventing premature aging. The paper does not show that eliminating p16Ink4a or p53 ameliorates the mice’s progeroid phenotypes; it presents accumulated DNA damage as a proposed mechanism rather than an established cause. (LLM, conf=0.88)

  cites Cao et al., 2003 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Varela et al., 2005 source
• Partly supported

  The main text (BubR1 mouse model and clearance experiments; Figs. 1–3, page not supplied) describes progeroid mice that accumulate senescent cells in certain tissues. It reports that p16Ink4a inactivation was known to delay selected phenotypes, and shows that clearing p16Ink4a-positive cells delays selected disorders. It does not attribute the mice’s premature ageing to extensive, persistent damage or report improvement following p53 elimination. (LLM, conf=0.88)

  cites Baker et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The “DNA Damage” discussion says that forms of DNA damage trigger senescence, while the paper reports that telomere-independent DNA-damage foci increase with organismal aging. The “Recording Mitogenic Stimulation by the INK4a/ARF Locus” discussion identifies the locus as an inducer of senescence and says it becomes derepressed with aging. Page numbers are not available in our copy. (LLM, conf=0.90)

  cites Collado et al., 2007 source

In the paper

“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”

What the sources say

• Partly supported

  The Neutrophils section (page not provided) says aging shifts hematopoietic progenitors toward the myeloid lineage at the expense of the lymphoid lineage, supporting the claim of reduced production of adaptive immune cells. It does not say that hematopoiesis declines overall or link that shift to increased anemia or myeloid malignancies. (LLM, conf=0.87)

  cites Shaw et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“GnRH treatment prevents aging-impaired neurogenesis and decelerates aging development in mice”

What the sources say

• Supported

  The section “GnRH treatment prevents aging-impaired neurogenesis” reports that GnRH substantially reversed diminished neurogenesis in old mice. The section “GnRH therapy decelerates aging development” reports reduced aging-related histological changes following prolonged GnRH treatment in mice. (LLM, conf=0.95)

  cites Zhang et al., 2013 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Rothwell et al., 2011 source
• Partly supported

  The Results report that aspirin increased survival in male mice, but not female mice. The Discussion describes an association between aspirin use and survival in very old humans; it does not establish that long-term aspirin administration promotes healthy aging in humans. The authors also say that further measures of age-related health are needed to determine whether the mouse survival effect reflects an effect on aging generally. (LLM, conf=0.85)

  cites Strong et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  The introduction (p. 5) describes the microbiota as important for intestinal homeostasis and links its composition to inflammation and immune-related ageing. The faecal-metabolome results (p. 8) associate microbiota composition with metabolites, but measure faecal water rather than systemic metabolic effects. The paper therefore supports the immune and metabolic connection, not the claim that it exerts systemic metabolic effects. (LLM, conf=0.84)

  cites Claesson et al., 2012 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The indexed passages contain a repository record and the paper’s title, but no substantive passage from the paper. Searches for immune-system function and systemic metabolic effects returned only that record, so our copy cannot verify either attributed effect. (LLM, conf=0.75)

  cites Ottaviani et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“The genomic stability systems also include specific mechanisms for maintaining the appropriate length and functionality of telomeres (which are the topic of a separate hallmark, see below), and for ensuring the integrity of mitochondrial DNA (mtDNA) (Blackburn et al., 2006; Kazak et al., 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites Blackburn et al., 2006 source
• ?Not checked — no full text of the sourcecites Kazak et al., 2012 source

In the paper

“This caveat is tempered by the extensive interconnectedness between the aging hallmarks, implying that experimental amelioration of one particular hallmark may impinge on others.”

In the paper

“This set of ideal requisites is met to varying degrees by the proposed hallmarks, an aspect that will be discussed in detail for each of them.”

In the paper

“Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution.”

In the paper

“Beyond its role in chromatin remodeling and DNA repair, SIRT1 also modulates proteostasis, mitochondrial function, nutrient-sensing pathways and inflammation (see below), illustrating the interconnectedness between aging hallmarks.”

In the paper

“There is extensive evidence that genomic damage accompanies aging and that its artificial induction can provoke aspects of accelerated aging.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Blackburn et al., 2006 source

In the paper

“Mammalian telomeric repeats are also enriched for these chromatin modifications, indicating that chromosome ends are assembled into heterochromatin domains (Gonzalo et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Gonzalo et al., 2006 source

In the paper

“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).”

In the paper

“Epigenetic changes involve alterations in DNA methylation patterns, post-translational modification of histones, and chromatin remodeling.”

In the paper

“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.”

In the paper

“Nuclear lamins constitute the major components of the nuclear lamina, and participate in genome maintenance by providing a scaffold for tethering chromatin and protein complexes that regulate genomic stability (Gonzalez-Suarez et al., 2009; Liu et al., 2005).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Gonzalez-Suarez et al., 2009 source
• ?Not checked — no full text of the sourcecites Liu et al., 2005 source

In the paper

“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.”

In the paper

“Mutant mice deficient in SIRT6 exhibit accelerated aging (Mostoslavsky et al., 2006), whereas male transgenic mice overexpressing Sirt6 have a longer lifespan than control animals, associated with reduced serum IGF-1 and other indicators of IGF-1 signaling (Kanfi et al., 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites Kanfi et al., 2012 source

In the paper

“Nevertheless, thus far there is no direct experimental demonstration that organismal lifespan can be extended by altering patterns of DNA methylation.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Kanfi et al., 2012 source
• ?Not checked — no full text of the sourcecites Mostoslavsky et al., 2006 source

In the paper

“Collectively, these results support the idea that sirtuins may act as metabolic sensors to control mitochondrial function and play a protective role against age-associated diseases.”

In the paper

“organisms with a constitutively decreased IIS can survive longer because they have lower rates of cell growth and metabolism, and hence lower rates of cellular damage”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Calabrese et al., 2011 source

In the paper

“However, similar evidence does not exist yet for the effects of rapamycin on mammalian aging, and other mechanisms such as inhibition of the ribosomal S6 protein kinase 1 (S6K1) implicated in protein synthesis (Selman et al., 2009), could contribute to explain the pro-longevity effects of rapamycin (see section on Deregulated Nutrient-sensing).”

What the sources say

• Not checked yetcites Selman et al., 2009 source

In the paper

“Thus, a decreased IIS is a common characteristic of both physiological and accelerated aging, while a constitutively decreased IIS extends longevity.”

In the paper

“Moreover, increased expression of the proteasome subunit RPN-6 by the FOXO transcription factor DAF-16 confers proteotoxic stress resistance and extends lifespan in C. elegans (Vilchez et al., 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites Vilchez et al., 2012 source

In the paper

“There is evidence that aging is associated with perturbed proteostasis, and experimental perturbation of proteostasis can precipitate age-associated pathologies.”

In the paper

“PGC-1α orchestrates a complex metabolic response that includes mitochondriogenesis, enhanced anti-oxidant defenses, and improved fatty acid oxidation”

What the sources say

• ?Not checked — no full text of the sourcecites Fernandez-Marcos and Auwerx, 2011 source

In the paper

“The other two nutrient sensors, AMPK and sirtuins, act in the opposite direction to IIS and mTOR, meaning that they signal nutrient scarcity and catabolism instead of nutrient abundance and anabolism. Accordingly, their up-regulation favors healthy aging.”

In the paper

“In aged organisms, this turnover system may become inefficient or may exhaust the regenerative capacity of progenitor cells, eventually resulting in the accumulation of senescent cells that may aggravate the damage and contribute to aging”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Rossi et al., 2007 source

In the paper

“This correlates with the accumulation of DNA damage (Rossi et al., 2007), and with the overexpression of cell cycle-inhibitory proteins such as p16INK4a”

What the sources say

• ?Not checked — no full text of the sourcecites Rossi et al., 2007 source
• ?Not checked — no full text of the sourcecites Janzen et al., 2006 source

In the paper

“This illustrates the difficulty of disentangling the mechanistic basis for the anti-aging activity of rapamycin, and underscores the interconnectedness between the different hallmarks of aging discussed here.”

In the paper

“the induction of INK4a during aging (see section on Cellular Senescence) and the decrease of serum IGF-1 (see section on Deregulated Nutrient-sensing), may both reflect an attempt of the organism to preserve the quiescence of stem cells”

In the paper

“Likewise, impaired kidney function can increase the risk of heart disease in humans (Sarnak et al., 2003).”

What the sources say

• ?Not checked — no full text of the sourcecites Sarnak et al., 2003 source

In the paper

“the accumulation of senescent cells with aging can reflect an increase in the rate of generation of senescent cells and/or a decrease in their rate of clearance”

In the paper

“what conceivably is the primary purpose of senescence, which is to prevent the propagation of damaged cells and to trigger their demise by the immune system”

In the paper

“mice with a mild and systemic increase in p16Ink4a, p19Arf or p53 tumor suppressors exhibit extended longevity, which cannot be accounted for by their lower cancer incidence”

What the sources say

• ?Not checked — no full text of the sourcecites Matheu et al., 2009 source
• ?Not checked — no full text of the sourcecites Matheu et al., 2007 source

In the paper

“Both p16INK4a and p19ARF are encoded by the same genetic locus, the INK4a/ARF locus.”

In the paper

“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”

In the paper

“We propose that cellular senescence is a beneficial compensatory response to damage that becomes deleterious and accelerates aging when tissues exhaust their regenerative capacity.”

In the paper

“Similar results were obtained in the skin, lung and spleen, but no changes were observed in heart, skeletal muscle and kidney”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2009 source

In the paper

“old INK4a−/− HSCs exhibit better engraftment capacity and increased cell cycle activity compared with old wild-type HSCs”

What the sources say

• ?Not checked — no full text of the sourcecites Janzen et al., 2006 source

In the paper

“one of the functions of the immune system is to recognize and eliminate senescent cells (see section on Stem Cell Exhaustion), as well as hyperploid cells that accumulate in aging tissues and premalignant lesions”

What the sources say

• ?Not checked — no full text of the sourcecites Davoli and de Lange, 2011 source
• ?Not checked — no full text of the sourcecites Senovilla et al., 2012 source

In the paper

“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”

In the paper

“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.”

In the paper

“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.”

In the paper

“Because the hallmarks co-occur during aging and are interconnected, understanding their exact causal network is an exciting challenge for future work.”

In the paper

“This is the case of DNA damage, including chromosomal aneuploidies, mitochondrial DNA mutations and telomere loss, epigenetic drift, and defective proteostasis.”

In the paper

“The primary hallmarks could be the initiating triggers whose damaging events progressively accumulate with time.”

In the paper

“likewise, an optimal nutrient-sensing and anabolism is obviously important for survival but in excess and during time can become pathological.”

In the paper

“Finally, the integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms.”

In the paper

“The common characteristic of the primary hallmarks is the fact that they are all unequivocally negative.”

In the paper

“A third category comprises the integrative hallmarks, stem cell exhaustion and altered intercellular communication, which directly affect tissue homeostasis and function.”