Mitochondrial and metabolic dysfunction in ageing and age-related diseases

In the paper

“In nematodes, pharmacological inhibition of PARP1 increases mitochondrial biogenesis and extends lifespan84.”

What the sources say

• Supported

  The Results report that PARP inhibitors extended worm lifespan by 15–23% and that AZD2281-treated worms had increased mitochondrial abundance, measured by the mtDNA/nDNA ratio. The paper identifies pme-1 as the worm PARP1 homolog and the major worm PARP activity. The drugs were pan-PARP inhibitors, rather than PARP1-selective inhibitors. (LLM, conf=0.88)

  cites [84] Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013). source

In the paper

“Moreover, mtDNA mutations have been associated with the development of chronic human diseases, such as atherosclerosis, hypertension, T2DM, cardiovascular disease and obesity175–178.”

What the sources say

• Not checked yetcites [175] Nomiyama, T. et al. Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients. Ann. N. Y. Acad. Sci. 1011, 193–204 (2004). source
• Not checked yetcites [176] Bhopal, R. S. & Rafnsson, S. B. Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations? Int. J. Epidemiol. 38, 1072–1081 (2009). source
• Not checked yetcites [177] Corral-Debrinski, M. et al. Hypoxemia is associated with mitochondrial DNA damage and gene induction: implications for cardiac disease. JAMA 266, 1812–1816 (1991). source
• Partly supported

  The abstract (p. 1) links mtDNA mutations to essential hypertension, and section 5 (p. 3) describes mutations associated with hypertension, type 2 diabetes, and coronary artery disease in one family. The paper also lists mtDNA mutations associated with cardiomyopathy (section 5, p. 4), supporting a cardiovascular-disease connection. Our copy does not link mtDNA mutations to atherosclerosis; obesity appears only in a reference title about mitochondrial genome polymorphisms (References, p. 6). (LLM, conf=0.87)

  cites [178] Ding, Y., Xia, B., Yu, J., Leng, J. & Huang, J. Mitochondrial DNA mutations and essential hypertension (review). Int. J. Mol. Med. 32, 768–774 (2013). sourceExperimental — accuracy not yet measured

In the paper

“However, results from human studies testing nicotinamide riboside supplementation at 2,000 mg per day showed that although safe, nicotinamide riboside does not improve insulin sensitivity and whole-body glucose metabolism in patients with obesity and insulin resistance259.”

What the sources say

• Supported

  The Abstract reports that 12 weeks of nicotinamide riboside at 2,000 mg/day appeared safe but did not improve insulin sensitivity or whole-body glucose metabolism in obese, insulin-resistant men. The Discussion also supports the safety finding. The study population was men, so the finding should not be read as established for all patients with obesity and insulin resistance. (LLM, conf=0.94)

  cites [259] Dollerup, O. L. et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am. J. Clin. Nutr. 108, 343–353 (2018). source

In the paper

“Moreover, NMN252 and nicotinamide riboside255, another NAD+ precursor, increased mitochondrial function and improved glucose homeostasis in obese mice.”

What the sources say

• Partly supported

  The Results section on glucose metabolism (page unavailable) reports that NMN improved impaired glucose tolerance in high-fat-diet-induced diabetic mice. The Discussion (page unavailable) only speculates that mitochondrial sirtuins might be involved; it does not show that NMN increased mitochondrial function. The separate citation attached to nicotinamide riboside is not assessed here. (LLM, conf=0.87)

  cites [252] Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011). sourceExperimental — accuracy not yet measured
• Supported

  The Results sections on NR supplementation and oxidative performance report enhanced mitochondrial function and better glucose disposal with lower insulin levels in NR-supplemented mice fed a high-fat diet. The citation to this paper is attached to nicotinamide riboside; the sentence cites a different source for NMN. The improvement in glucose tolerance itself was slight and not statistically significant. (LLM, conf=0.86)

  cites [255] Canto, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012). source

In the paper

“By reducing the excess of ingested calories, calorie restriction interventions move the ETC away from a reduced state, lower ROS production, induce OXPHOS and antioxidant defences, prevent age-related diseases and increase lifespan14.”

What the sources say

• Not checked yetcites [14] Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005). source

In the paper

“This environment favours ROS production, mitochondrial DNA (mtDNA) mutagenesis and, consequently, premature cell death.”

In the paper

“When carbohydrates and, consequently, calories are in excess, OXPHOS and antioxidant defences are downregulated, and the electron transport chain (ETC) remains in a chronically reduced state.”

In the paper

“In DAF-2 mutants, age-related changes in mitochondrial morphology and density are mitigated, and mitochondrial trafficking is maintained at under normal levels in adulthood21.”

What the sources say

• Not checked yetcites [21] Morsci, N. S., Hall, D. H., Driscoll, M. & Sheng, Z. H. Age-related phasic patterns of mitochondrial maintenance in adult Caenorhabditis elegans neurons. J. Neurosci. 36, 1373–1385 (2016). source

In the paper

“which was discovered after it was shown that rapamycin is able to inhibit mTORC1 via binding to the protein FKBP12 (REFS31,32).”

What the sources say

• Not checked yetcites [31] Loewith, R. et al. Two TOR complexes only one of which is rapamycin sensitive have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002). source
• Not checked yetcites [32] Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007). source

In the paper

“Mammalian TOR (mTOR) is a ubiquitously expressed serine–threonine protein kinase, belonging to the PI3K family, that has a vital role in regulating cytoplasmic nutritional and growth factor status, as well as cellular energy levels and overall cellular function30.”

What the sources say

• Not checked yetcites [30] Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017). source

In the paper

“Subsequent studies also elucidated this signalling pathway and indicated that activated AMPK phosphorylates PGC1α, which consequently induces mitochondrial gene expression41.”

What the sources say

• Not checked yetcites [41] Jäger, S., Handschin, C., St-Pierre, J. & Spiegelman, B. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007). source

In the paper

“Suppression of the insulin–insulin-like growth factor 1 (IGF1) signalling (IIS) pathway dramatically extends lifespan in multiple organisms, which suggests that it is an evolutionarily conserved mechanism16.”

What the sources say

• Not checked yetcites [16] Fontana, L., Partridge, L. & Longo, V. Extending healthy life span–from yeast to humans. Science 328, 321–326 (2010). source

In the paper

“AMPK is considered the primary sensor of cellular AMP to ATP and ADP to ATP ratios and a key regulator of cellular energy homeostasis and metabolism39.”

What the sources say

• Not checked yetcites [39] Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018). source

In the paper

“mTOR is present in two complexes, mTORC1 (associated with ‘raptor’) and mTORC2 (associated with ‘rictor’), accounting for the diversity, specificity and selectivity of rapamycin-mediated inhibition of TOR signalling”

What the sources say

• Not checked yetcites [31] Loewith, R. et al. Two TOR complexes only one of which is rapamycin sensitive have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002). source
• Not checked yetcites [32] Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007). source

In the paper

“Therefore, mitochondria might be the critical mediator for the effects of mTOR inhibition on longevity, and might represent a notable therapeutic target in ageing and age-related diseases.”

In the paper

“Extensive overlap in gene expression has been found between the C. elegans insulin receptor DAF-2 mutant and long-lived mitochondrial mutant strains17, with the DAF-2 mutant showing an overall decrease in mitochondrial protein turnover18.”

What the sources say

• Not checked yetcites [17] Senchuk, M. M. et al. Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans. PLoS Genet. 14, e1007268 (2018). source
• Not checked yetcites [18] Dhondt, I. et al. FOXO/DAF-16 activation slows down turnover of the majority of proteins in C. elegans. Cell Rep. 16, 3028–3040 (2016). source

In the paper

“In addition, increased ROS levels induced expression of antioxidant enzymes, followed by a decrease in ROS levels20.”

What the sources say

• Not checked yetcites [20] Zarse, K. et al. Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab. 15, 451–465 (2012). source

In the paper

“Moreover, DAF-2 mutants have increased abundance of proteins involved in OXPHOS, increased respiratory capacity and increased membrane potential19.”

What the sources say

• Not checked yetcites [19] Brys, K., Castelein, N., Matthijssens, F., Vanfleteren, J. R. & Braeckman, B. P. Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans. BMC Biol. 8, 91 (2010). source

In the paper

“Likewise, fat-specific insulin receptor knockout (FIRKO) mice have increased lifespan compared with wild-type mice despite having a leaner phenotype from a young age (3 months of age) and normal food intake throughout life27.”

What the sources say

• Not checked yetcites [27] Blüher, M., Kahn, B. & Kahn, C. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003). source

In the paper

“Deletion of the mTORC1 component raptor in mouse skeletal muscle affects PGC1α expression, reducing oxidative capacity36, and consequently inducing premature ageing.”

What the sources say

• Not checked yetcites [36] Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008). source

In the paper

“Thus, these results suggest that inhibition of IIS improves mitochondrial bioenergetics together with a ROS-mediated adaptive response, contributing to the lifespan extension effects observed in C. elegans.”

In the paper

“In the context of mitochondrial diseases, inhibition of mTOR using rapamycin improves mitochondrial function and alleviates symptoms of Leigh syndrome37, a disease caused by mtDNA deletions, in a mouse model of the syndrome.”

What the sources say

• Not checked yetcites [37] Johnson, S. et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342, 1524–1529 (2013). source

In the paper

“Interestingly, increased expression of mitochondrial biogenesis transcription driver HAP4 resulted in lifespan extension under normal caloric conditions in yeast (Saccharomyces cerevisiae), with calorie restriction failing to further extend this longevity benefit11.”

What the sources say

• Not checked yetcites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source

In the paper

“SIRT4 interacts with adenine nucleotide translocator, possibly regulating the ADP to ATP ratio and mitochondrial physiology54.”

What the sources say

• Not checked yetcites [54] Ahuja, N. et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–33592 (2007). source

In the paper

“These findings have helped guide the field to hypothesize that ROS production might not be the leading cause of the phenotypes correlated with ageing and that other factors might contribute.”

In the paper

“Evidence for a contribution of mtDNA mutations to the mammalian ageing phenotypes has come from the mtDNA mutator mouse, which carries a mutated, proofreading-deficient form of the nuclear-encoded mtDNA polymerase (POLGγ).”

What the sources say

• Not checked yetcites [66] Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). source

In the paper

“Moreover, it has been demonstrated that ageing phenotypes (such as spine curvature, reduced body weight and hair loss) and lifespan can be influenced by mtDNA mutation levels in mtDNA mutator mice69 and surprisingly also in mice with maternally-inherited mtDNA mutations but an otherwise wild-type nuclear genome70.”

What the sources say

• Not checked yetcites [69] Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013). source
• Not checked yetcites [70] Ross, J. M., Coppotelli, G., Hoffer, B. J. & Olson, L. Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci. Rep. 4, 6569 (2014). source

In the paper

“Notably, SIRT3 regulates ATP levels in multiple tissues52, as well as AMPK activation53.”

What the sources say

• Not checked yetcites [52] Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008). source
• Not checked yetcites [53] Palacios, O. M. et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging 1, 771–783 (2009). source

In the paper

“Closely linked to mitochondrial ROS production, the number of mtDNA mutations is known to increase with age63.”

What the sources say

• Not checked yetcites [63] Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927–6933 (1990). source

In the paper

“In 1972, Harman expanded the free radical theory of ageing with the ‘mitochondrial theory of ageing’, which included the possibility that mtDNA mutations might in fact be the drivers behind the mitochondrial dysfunction observed during ageing61.”

What the sources say

• Not checked yetcites [61] Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145–147 (1972). source

In the paper

“The mtDNA mutator mouse was shown to accumulate considerable levels of mtDNA mutations and deletions and to recapitulate several signs of premature ageing, such as reduced lifespan, reduced fertility, anaemia, sarcopenia, osteoporosis, hair greying, hair loss66, hearing loss67 and elevated lactate levels68.”

What the sources say

• Not checked yetcites [66] Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). source
• Not checked yetcites [67] Niu, X., Trifunovic, A., Larsson, N. G. & Canlon, B. Somatic mtDNA mutations cause progressive hearing loss in the mouse. Exp. Cell Res. 313, 3924–3934 (2007). source
• Not checked yetcites [68] Ross, J. M. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc. Natl Acad. Sci. USA 107, 20087–20092 (2010). source

In the paper

“However, while some reports favour the idea that mitochondrial mutations contribute to ageing and age-related diseases64, others have questioned this hypothesis due to the level of mutations observed65.”

What the sources say

• Not checked yetcites [64] Linnane, A. W., Ozawa, T., Marzuki, S. & Tanaka, M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642–645 (1989). source
• Not checked yetcites [65] Khrapko, K. & Vijg, J. Mitochondrial DNA mutations and aging: devils in the details? Trends Genet. 25, 91–98 (2009). source

In the paper

“The resulting availability of NAD+ increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination11,46, a known cause of ageing in yeast47.”

What the sources say

• Not checked yetcites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source
• Not checked yetcites [46] Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction and stress. Nature 423, 181–185 (2003). source
• Not checked yetcites [47] Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 91, 1033–1042 (1997). source

In the paper

“The accumulation of mitochondrial oxidative damage, which is the basis for Harman’s ‘free radical theory of ageing’56, has been suggested as a driver of mitochondrial dysfunction and the observed age-related decline in organ function during ageing.”

What the sources say

• Not checked yetcites [56] Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956). source

In the paper

“Failure to regulate energy homeostasis by these pathways is highly linked with mitochondrial dysfunction, which ultimately leads to age-related metabolic diseases.”

In the paper

“However, while several studies have supported the free radical theory of ageing57,58, others have shown that increased ROS production does not always shorten lifespan59.”

What the sources say

• Not checked yetcites [57] Melov, S. et al. Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics. J. Neurosci. 21, 8348–8353 (2001). source
• Not checked yetcites [58] Kirby, K., Hu, J., Hilliker, A. J. & Phillips, J. P. RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proc. Natl Acad. Sci. USA 99, 16162–16167 (2002). source
• Not checked yetcites [59] Van Raamsdonk, J. M. & Hekimi, S. Superoxide dismutase is dispensable for normal animal lifespan. Proc. Natl Acad. Sci. USA 109, 5785–5790 (2012). source

In the paper

“Analysis of an ATM mouse model showed dysfunctional mitochondria with increased ROS levels and the accumulation of damaged mitochondria87.”

What the sources say

• Not checked yetcites [87] Valentin-vega, Y. A. et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119, 1490–1500 (2012). source

In the paper

“Indeed, deletion of the Parp1 gene in mice increases NAD+ levels, SIRT1 activity and mitochondrial biogenesis83.”

What the sources say

• Not checked yetcites [83] Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011). source

In the paper

“Moreover, most of the mitochondrial proteins are encoded by nuclear DNA, and mutations on those genes are typically associated with mitochondrial diseases78.”

What the sources say

• Not checked yetcites [78] Wilkins, H. M. et al. in The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms 369–414 (Elsevier, 2018). source

In the paper

“Cellular senescence is characterized by an irreversible cell cycle arrest, changes in gene expression, tumour suppression activation, altered chromatin, resistance to apoptosis and increased protein synthesis89.”

What the sources say

• Not checked yetcites [89] Tchkonia, T., Zhu, Y., Deursen, J. V., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

In the paper

“Genomic instability induced by single-strand breaks or double-strand breaks triggering the DNA damage response (DDR) is a hallmark of ageing2, and can arise from both exogenous and endogenous sources79.”

What the sources say

• Not checked yetcites [2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). source
• Not checked yetcites [79] Hoeijmakers, J. H. J. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009). source

In the paper

“Similarly, Atm−/− mice also have mitochondrial defects and interventions based on NAD+ supplementation88 attenuate their health decline.”

What the sources say

• Not checked yetcites [88] Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016). source

In the paper

“Cellular senescence leads to decreased mitochondrial membrane potential, increased proton leakage and increased ROS production94, thus enhancing DNA damage and DDR95.”

What the sources say

• Not checked yetcites [94] Passos, J. F. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5, e110 (2007). source
• Not checked yetcites [95] Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010). source

In the paper

“However, the role of mtDNA mutations as a primary driver of the ageing process is still debated, in part because the number of mutations observed in normal aged tissues is seemingly below the threshold required to affect mitochondrial function71.”

What the sources say

• Not checked yetcites [71] Vermulst, M. et al. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39, 540–543 (2007). source

In the paper

“Pharmacological NAD+ supplementation or inhibition of PARP1 was able to re-establish SIRT1 activity and recover mitochondrial homeostasis85,86.”

What the sources say

• Not checked yetcites [85] Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014). source
• Not checked yetcites [86] Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab. 20, 840–855 (2014). source

In the paper

“Moreover, cells undergoing senescence display altered mitochondrial metabolite homeostasis96, as well as decreased fatty acid oxidation, leading to accumulation of lipids97.”

What the sources say

• Not checked yetcites [96] Correia-Melo, C. & Passos, J. F. Mitochondria: are they causal players in cellular senescence? Biochim. Biophys. Acta 1847, 1373–1379 (2015). source
• Not checked yetcites [97] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source

In the paper

“Activated PARP1 will consume NAD+, generating PAR through a process called PARylation82.”

What the sources say

• Not checked yetcites [82] Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012). source

In the paper

“That said, patients with HIV, who also present with phenotypes of premature ageing72 and premature age-associated cardiovascular disease73, have mitochondrial mutations and OXPHOS dysfunction74, possibly caused by anti-retroviral drugs that inhibit POLGγ75.”

What the sources say

• Not checked yetcites [72] Desquilbet, L. et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J. Gerontol. A Biol. Sci. Med. Sci. 62, 1279–1286 (2007). source
• Not checked yetcites [73] Guaraldi, G. et al. Coronary aging in HIV-infected patients. Clin. Infect. Dis. 49, 1756–1762 (2009). source
• Not checked yetcites [74] Payne, B. A. I. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat. Genet. 43, 806–810 (2011). source

In the paper

“Nuclear DNA repair is energy-demanding80, and persistent DNA damage can lead to mitochondrial dysfunction and metabolic deficits76.”

What the sources say

• Not checked yetcites [76] Fang, E. F. et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17, 308–321 (2016). source
• Not checked yetcites [80] Chaudhuri, A. R. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017). source

In the paper

“No universal marker has been discovered for senescent cells but cell cycle arrest, DDR, β-galactosidase activity and the pro-inflammatory senescence-associated secretory phenotype are common features of cells undergoing senescence90.”

What the sources say

• Not checked yetcites [90] Campisi, J. & D’Adda Di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007). source

In the paper

“Indeed, an association between dyslipidaemia and oxidized LDL has been observed in individuals with prediabetes122.”

What the sources say

• Not checked yetcites [122] Kopprasch, S. et al. In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance. Diabetes 51, 3102–3106 (2002). source

In the paper

“During senescence, mitochondrial biogenesis is upregulated, leading to an unhealthy mitochondrial network.”

What the sources say

• Not checked yetcites [95] Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010). source
• Not checked yetcites [98] Mai, S., Klinkenberg, M., Auburger, G., Bereiter-Hahn, J. & Jendrach, M. Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J. Cell Sci. 123, 917–926 (2010). source

In the paper

“An excess in total body mass, especially visceral adipose tissue, is associated with increased morbidity119 as well as metabolic inflexibility120, a phenomenon caused by the inability to transition between fatty acid and glucose metabolism.”

What the sources say

• Not checked yetcites [119] Matsumoto, A. M. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J. Gerontol. A. Biol. Sci. Med. Sci. 57, M76–M99 (2002). source
• Not checked yetcites [120] Griffin, T. M., Humphries, K. M., Kinter, M., Lim, H. Y. & Szweda, L. I. Nutrient sensing and utilization: getting to the heart of metabolic flexibility. Biochimie 124, 74–83 (2015). source

In the paper

“Both 5-mC and 5-hmC have been found in mtDNA, as well as DNMT3A and B DNA methyltransferases101–103.”

What the sources say

• Not checked yetcites [101] Chestnut, B. A. et al. Epigenetic regulation of motor neuron cell death through DNA methylation. J. Neurosci. 31, 16619–16636 (2011). source
• Not checked yetcites [102] Bellizzi, D. et al. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. DNA Res. 20, 537–547 (2013). source
• Not checked yetcites [103] Wong, M. et al. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front. Cell Neurosci. 7, 279 (2013).

In the paper

“The metabolic syndrome, which occurs increasingly with age, is associated with obesity, hyperglycaemia, dyslipidaemia, insulin resistance and cardiovascular diseases117,118.”

What the sources say

• Not checked yetcites [117] Haslam, D. W. & James, W. P. T. Obesity. Lancet 366, 1197–1209 (2005). source
• Not checked yetcites [118] Bhatti, G. K., Bhadada, S. K., Vijayvergiya, R., Mastana, S. S. & Bhatti, J. S. Metabolic syndrome and risk of major coronary events among the urban diabetic patients: North Indian Diabetes and Cardiovascular Disease Study–NIDCVD-2. J. Diabetes Complicat. 30, 72–78 (2016). source

In the paper

“Additionally, mtDNA analysis showed that the haplogroup N9A is likely to be protective against the metabolic syndrome in Japanese women128, as well as being protective against T2DM in Japanese and Korean populations129.”

What the sources say

• Not checked yetcites [128] Tanaka, M. et al. Women with mitochondrial haplogroup N9a are protected against metabolic syndrome. Diabetes 56, 518–521 (2007). source
• Not checked yetcites [129] Fuku, N. et al. Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am. J. Hum. Genet. 80, 407–415 (2007). source

In the paper

“In islets from patients with T2DM, the ATP content, and the increase in the ATP to ADP ratio stimulated by glucose, was lower than in islets from control individuals143.”

What the sources say

• Not checked yetcites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

In the paper

“Increased ROS levels due to hyperglycaemia activate UCP2, resulting in proton leak across the mitochondrial inner membrane, which leads to reduced ATP synthesis and oxidative damage to the membrane, cytochrome c release and the induction of apoptosis149.”

What the sources say

• Not checked yetcites [149] Butler, A. et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 102, 1295–1297 (2003).

In the paper

“Apart from variations in mtDNA, patients with the metabolic syndrome show a reduced number of mtDNA copies in peripheral blood and adipose tissue132, a physiological change typically observed before the development of T2DM133.”

What the sources say

• Not checked yetcites [132] Mozhey, O. I. et al. Evaluating the number of mitochondrial DNA copies in leukocytes and adipocytes from metabolic syndrome patients: pilot study. Mol. Biol. 48, 590–593 (2014). source
• Not checked yetcites [133] Lee, H. K. et al. Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res. Clin. Pract. 42, 161–167 (1998). source

In the paper

“Mitochondrial dysfunction is increasingly thought to be a central contributor to β-cell failure in the evolution of T2DM, with ROS production induced by metabolic stress as a key event leading to β-cell failure.”

In the paper

“Furthermore, in a white family, the T4291C mtDNA mutation has been associated with the metabolic syndrome, and the T16189C mtDNA variant has been reported to be associated with abnormalities in body mass, insulin resistance and increased cardiomyopathy, as well as increased risk of the metabolic syndrome130.”

What the sources say

• Not checked yetcites [130] Palmieri, V. O. et al. T16189C mitochondrial DNA variant is associated with metabolic syndrome in Caucasian subjects. Nutrition 27, 773–777 (2011). source

In the paper

“Mitochondrial dynamics are crucial to T2DM and related vascular complications, given the central role of mitochondria in ATP production, insulin secretion and ROS formation134.”

What the sources say

• Not checked yetcites [134] Kytövuori, L. et al. A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. J. Neurol. 263, 2188–2195 (2016). source

In the paper

“Moreover, increased expression of uncoupling protein 2 (UCP2), complex I and ATP synthase have been observed in islets from patients with T2DM143.”

What the sources say

• Not checked yetcites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

In the paper

“In white adipose tissue, the uncoupling of OXPHOS has been shown to decrease fatty acid synthesis156, leading to increased energy expenditure and reduced lipogenesis, which provides an important energy source to cells through oxidation of fatty acids157.”

What the sources say

• Not checked yetcites [156] Rossmeisl, M. et al. Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue. FASEB J. 14, 1793–1800 (2000). source
• Not checked yetcites [157] Serra, D., Mera, P., Malandrino, M. I., Mir, J. F. & Herrero, L. Mitochondrial fatty acid oxidation in obesity. Antioxid. Redox Signal. 19, 269–284 (2013). source

In the paper

“Decreased ATP content, impaired mitochondrial bioenergetics and increased ROS generation have all been found in patients with non-alcoholic steatohepatitis, and in fatty liver models in the rat161–163.”

What the sources say

• Not checked yetcites [161] Cortez-Pinto, H. et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282, 1659–1664 (1999). source
• Not checked yetcites [162] Teodoro, J., Rolo, A. P., Oliveira, P. J. & Palmeira, C. M. Decreased ANT content in Zucker fatty rats: relevance for altered hepatic mitochondrial bioenergetics in steatosis. FEBS Lett. 580, 2153–2157 (2006). source
• Not checked yetcites [163] Teodoro, J. S., Rolo, A. P., Duarte, F. V., Simões, A. M. & Palmeira, C. M. Differential alterations in mitochondrial function induced by a choline-deficient diet: understanding fatty liver disease progression. Mitochondrion 8, 367–376 (2008). source

In the paper

“While there is no evidence for mitochondrial depletion in β-cells from patients with T2DM, the mitochondrial density volume is considerably higher in islets from patients with T2DM than in islets from those without T2DM, with both morphological and functional abnormalities that have not been observed in β-cells from control individuals143.”

What the sources say

• Not checked yetcites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

In the paper

“Both desensitization and depletion of β-cells are reversible states; however, if the hyperglycaemic situation persists, it can lead to the irreversible loss of insulin production and, ultimately, the death of β-cells142.”

What the sources say

• Not checked yetcites [142] DeFronzo, R. A. & Abdul-Ghani, M. A. Preservation of β-cell function: the key to diabetes prevention. J. Clin. Endocrinol. Metab. 96, 2354–2366 (2011). source

In the paper

“Age-associated liver diseases, such as NAFLD, have been described as hepatic examples of the metabolic syndrome152, where insulin resistance is also a key pathological feature.”

What the sources say

• Not checked yetcites [152] Paschos, P. & Paletas, K. Non-alcoholic fatty liver disease and the metabolic syndrome. Hippokratia 13, 9–19 (2009).

In the paper

“Decreased mitochondrial oxidative capacity and mitochondrial content, reduced oxidative capacity, defective lipid metabolism and increased lipid peroxidation are also seen in skeletal muscle from patients with obesity and insulin resistance compared with healthy and lean individuals136,137.”

What the sources say

• Not checked yetcites [136] Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002). source
• Not checked yetcites [137] Schrauwen, P., Schrauwen-Hinderling, V., Hoeks, J. & Hesselink, M. K. C. Mitochondrial dysfunction and lipotoxicity. Biochim. Biophys. Acta Biophys. Acta 1801, 266–271 (2010). source

In the paper

“Studies of obesity in rats and a T2DM model known as the OLETF obese hyperphagic rat showed that reduced hepatic mitochondrial content and function precede the development of NAFLD and insulin resistance, supporting a crucial role for mitochondria in the pathophysiology of NAFLD160.”

What the sources say

• Not checked yetcites [160] Rector, R. S. et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J. Hepatol. 52, 727–736 (2010). source

In the paper

“Unlike the adaptive immune response, the innate immune response is rapid (<90 h) and non-specific, being activated by a broad range of molecules that comprise viruses and bacteria.”

In the paper

“Additional work has revealed that p66Shc activation is involved in adipogenesis, insulin resistance and cardiovascular complications associated with diabetes mellitus187–189.”

What the sources say

• Not checked yetcites [187] Camici, G. G. et al. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl Acad. Sci. USA 104, 5217–5222 (2007). source
• Not checked yetcites [188] Berniakovich, I. et al. p66Shc-generated oxidative signal promotes fat accumulation. J. Biol. Chem. 283, 34283–34293 (2008). source
• Not checked yetcites [189] Paneni, F., Costantino, S. & Cosentino, F. p66Shc-induced redox changes drive endothelial insulin resistance. Atherosclerosis 236, 426–429 (2014). source

In the paper

“Innate immunity has a central role in the inflammatory process and coordinates the three stages of inflammation: initiation, propagation and resolution195.”

What the sources say

• Not checked yetcites [195] Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M. & Teixeira, M. M. Resolution of inflammation: what controls its onset? Front. Immunol. 7, 160 (2016). source

In the paper

“One of the strongest alarmins released by stressed mitochondria is mtDNA, which has emerged as a strong activator of innate immunity, particularly of the interferon signalling pathway201.”

What the sources say

• Not checked yetcites [201] West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017). source

In the paper

“Indeed, elevated ROS levels lead to endothelial dysfunction171, an early event in atherosclerosis pathogenesis that occurs mainly in atherosclerotic lesion formation172,173.”

What the sources say

• Not checked yetcites [171] Thomas, S. R., Witting, P. K. & Drummond, G. R. Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 10, 1713–1765 (2008). source
• Not checked yetcites [172] Abe, J. & Berk, B. C. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc. Med. 8, 59–64 (1998). source
• Not checked yetcites [173] Grootaert, M. O. J., Roth, L., Schrijvers, D. M., De Meyer, G. R. Y. & Martinet, W. Defective autophagy in atherosclerosis: to die or to senesce? Oxid. Med. Cell. Longev. 2018, 7687083 (2018). source

In the paper

“Under conditions of an imbalanced redox state, increased mitochondrial ROS production might lead to modifications of the arterial walls180, followed by an inflammatory environment181.”

What the sources say

• Not checked yetcites [180] Naik, E. & Dixit, V. M. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J. Exp. Med. 208, 417–420 (2011). source
• Not checked yetcites [181] Davies, J. M. S. et al. The Oxygen Paradox, the French Paradox, and age-related diseases. GeroScience 39, 499–550 (2017). source

In the paper

“Induction of Ser26 phosphorylation of p66Shc by protein kinase C-β (PKCβ) triggers the transport of p66Shc from the cytosol to mitochondria, where it promotes ROS accumulation by oxidizing cytochrome c184, ultimately leading to apoptosis.”

What the sources say

• Not checked yetcites [184] Giorgio, M. et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233 (2005). source

In the paper

“In one study, 16-month-old MnSOD+/− mice consistently showed elevated ROS production and mtDNA damage, followed by the development of dramatic endothelial dysfunction182.”

What the sources say

• Not checked yetcites [182] Wenzel, P. et al. Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc. Res. 80, 280–289 (2008). source

In the paper

“Mutant p66Shc−/− mice have been reported to be resistant to oxidative stress and to have an increased lifespan185, as well as reduced age-dependent endothelial dysfunction186.”

What the sources say

• Not checked yetcites [185] Migliaccio, E. et al. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999). source

In the paper

“Alarmins bind to and activate PRRs, thus triggering an immune response and propagating the inflammation199.”

What the sources say

• Not checked yetcites [199] Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020). source

In the paper

“Moreover, vascular levels of p66Shc were increased in animal models of obesity and had a role in endothelial insulin resistance189, an effect restored when p66Shc was silenced in vivo189.”

What the sources say

• Not checked yetcites [189] Paneni, F., Costantino, S. & Cosentino, F. p66Shc-induced redox changes drive endothelial insulin resistance. Atherosclerosis 236, 426–429 (2014). source

In the paper

“Oxidative stress, a characteristic of T2DM, hypertension and atherosclerosis, is also the dominant feature of vascular ageing170.”

What the sources say

• Not checked yetcites [170] Ding, Y. N., Tang, X., Chen, H. Z. & Liu, D. P. Epigenetic regulation of vascular aging and age-related vascular diseases. Adv. Exp. Med. Biol. 1086, 55–75 (2018). source

In the paper

“Thus, uncoupling of OXPHOS and increased ROS generation, with oxidative damage to ETC complexes and mtDNA, further compromise mitochondrial function and perpetuate ROS formation, thus destabilizing the redox environment of the cell.”

In the paper

“Pathogen-associated molecular patterns (PAMPs) share conserved features among microbes not present in mammalian cells196.”

What the sources say

• Not checked yetcites [196] Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006). source

In the paper

“Once these PAMPs are recognized by specific receptors belonging to the pattern recognition receptor (PRR) family, an immune response is activated and escalates to induce inflammation and the release of numerous cytokines for recruitment of the more specific adaptive immune system197.”

What the sources say

• Not checked yetcites [197] Jain, A. & Pasare, C. Innate control of adaptive immunity: beyond the three-signal paradigm. J. Immunol. 198, 3791–3800 (2017). source

In the paper

“In one study using animal models and human samples from patients with obesity undergoing elective surgery, it was demonstrated that reduced p66Shc levels could protect from obesity but failed to prevent obesity-associated metabolic dysfunction192, highlighting the need for further studies to dissect the role of p66Shc in metabolism.”

What the sources say

• Not checked yetcites [192] Ciciliot, S. et al. p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans. Diabetologia 58, 2352–2360 (2015). source

In the paper

“Similarly, genetic ablation of mitochondrial GPX1 in mice triggered noticeable vascular dysfunction, coinciding with increased oxidative stress and impaired nitric oxide metabolism183, thus linking perturbations in redox status to vascular ageing.”

What the sources say

• Not checked yetcites [183] Oelze, M. et al. Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63, 390–396 (2014). source

In the paper

“Ultrastructural changes include the presence of enlarged mitochondria, loss of cristae organization and crystalline inclusion bodies in the matrix in patients with NAFLD164.”

What the sources say

• Not checked yetcites [164] Shami, G. J. et al. Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease. Sci. Rep. 11, 3319 (2021). source

In the paper

“Consequently, work has shown that p66Shc−/− mice are protected against streptozotocin-induced diabetic cardiomyopathy191, diabetes mellitus-induced vascular endothelial dysfunction and oxidative stress187.”

What the sources say

• Not checked yetcites [187] Camici, G. G. et al. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl Acad. Sci. USA 104, 5217–5222 (2007). source
• Not checked yetcites [191] Rota, M. et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ. Res. 99, 42–52 (2006). source

In the paper

“Several alarmins consist of mitochondrial molecules, and the ability of these molecules to activate PRRs is dependent on their similarity to bacterial components, reaffirming once again the prokaryotic origin of mitochondria200.”

What the sources say

• Not checked yetcites [200] Roger, A. J., Muñoz-Gómez, S. A. & Kamikawa, R. The origin and diversification of mitochondria. Curr. Biol. 27, R1177–R1192 (2017). source

In the paper

“Vascular ageing is the major risk factor for vascular diseases and health status in the aged population168, contributing to the age-dependent increased risk of pathological conditions of vascular dysfunction, such as hypertension and atherosclerosis, and are also characteristic of cardiovascular risk factors, such as obesity, smoking and a sedentary lifestyle169.”

What the sources say

• Not checked yetcites [168] El Assar, M., Angulo, J. & Rodríguez-Mañas, L. Oxidative stress and vascular inflammation in aging. Free Radic. Biol. Med. 65, 380–401 (2013). source
• Not checked yetcites [169] Jani, B. & Rajkumar, C. Ageing and vascular ageing. Postgrad. Med. J. 82, 357–362 (2006). source

In the paper

“Interestingly, a newly reported molecule, imeglimin, a tetrahydrotriazine-containing oral glucose-lowering agent, decreased ROS production and prevented hyperglycaemia-induced cell death via complex l by inhibiting reverse electron transfer-mediated ROS production in preclinical studies240, and its efficacy and favourable safety and tolerability profile have been confirmed in patients with T2DM241”

What the sources say

• Not checked yetcites [240] Detaille, D. et al. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov. 2, 15072 (2016). source