Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.
Ageing is the main risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD).
Tissues composed primarily of postmitotic cells, such as the brain, are especially sensitive to the effects of ageing.
Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication — correlate with susceptibility to neurodegenerative disease.
NAD+ deficiency is a key biomarker for mitochondrial dysfunction, and agents that elevate intracellular NAD+ have shown promising results against many features of neurodegeneration.
Genomic instability, mitophagy, cellular senescence, protein aggregation and inflammation are being explored as therapeutic targets for neurodegenerative disease.
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Rose, M. R. Adaptation, aging, and genomic information. Aging 1, 444–450 (2009).
Carmona, J. J. & Michan, S. Biology of healthy aging and longevity. Rev. Invest. Clin. 68, 7–16 (2016).
Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement. 14, 367–429 (2018).
Wyss-Coray, T. Ageing, neurodegeneration and brain rejuvenation. Nature 539, 180–186 (2016).
Elobeid, A., Libard, S., Leino, M., Popova, S. N. & Alafuzoff, I. Altered proteins in the aging brain. J. Neuropathol. Exp. Neurol. 75, 316–325 (2016).
Dean, D. C., 3rd et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 71, 11–22 (2014).
Schaefers, A. T. & Teuchert-Noodt, G. Developmental neuroplasticity and the origin of neurodegenerative diseases. World J. Biol. Psychiatry 17, 587–599 (2016).
Nussbaum, R. L. & Ellis, C. E. Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med. 348, 1356–1364 (2003).
Hy, L. X. & Keller, D. M. Prevalence of AD among whites: a summary by levels of severity. Neurology 55, 198–204 (2000).
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Primers 3, 17013 (2017).
Mehta, P. et al. Prevalence of amyotrophic lateral sclerosis – United States, 2014. MMWR Morb. Mortal. Wkly. Rep. 67, 216–218 (2018).
Robinson, J. L. et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181–2193 (2018).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Chow, H. M. & Herrup, K. Genomic integrity and the ageing brain. Nat. Rev. Neurosci. 16, 672–684 (2015).
Madabhushi, R., Pan, L. & Tsai, L. H. DNA damage and its links to neurodegeneration. Neuron 83, 266–282 (2014).
Jeppesen, D. K., Bohr, V. A. & Stevnsner, T. DNA repair deficiency in neurodegeneration. Prog. Neurobiol. 94, 166–200 (2011).
Thanan, R. et al. Oxidative stress and its significant roles in neurodegenerative diseases and cancer. Int. J. Mol. Sci. 16, 193–217 (2015).
McKinnon, P. J. Maintaining genome stability in the nervous system. Nat. Neurosci. 16, 1523–1529 (2013).
Maynard, S., Schurman, S. H., Harboe, C., de Souza-Pinto, N. C. & Bohr, V. A. Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30, 2–10 (2009).
Tell, G. & Demple, B. Base excision DNA repair and cancer. Oncotarget 6, 584–585 (2015).
Leandro, G. S., Sykora, P. & Bohr, V. A. The impact of base excision DNA repair in age-related neurodegenerative diseases. Mutat. Res. 776, 31–39 (2015).
Akbari, M., Morevati, M., Croteau, D. & Bohr, V. A. The role of DNA base excision repair in brain homeostasis and disease. DNA Repair 32, 172–179 (2015).
Fang, E. F. et al. NAD(+) in aging: molecular mechanisms and translational implications. Trends Mol. Med. 23, 899–916 (2017).
Herrmann, M., Pusceddu, I., Marz, W. & Herrmann, W. Telomere biology and age-related diseases. Clin. Chem. Lab. Med. 56, 1210–1222 (2018).
Eitan, E., Hutchison, E. R. & Mattson, M. P. Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci. 37, 256–263 (2014).
Bradley-Whitman, M. A. & Lovell, M. A. Epigenetic changes in the progression of Alzheimer’s disease. Mech. Ageing Dev. 134, 486–495 (2013).
Hwang, J. Y., Aromolaran, K. A. & Zukin, R. S. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat. Rev. Neurosci. 18, 347–361 (2017).
Tanaka, K. & Matsuda, N. Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim. Biophys. Acta 1843, 197–204 (2014).
Johri, A. & Beal, M. F. Mitochondrial dysfunction in neurodegenerative diseases. J. Pharmacol. Exp. Ther. 342, 619–630 (2012).
Keogh, M. J. & Chinnery, P. F. Mitochondrial DNA mutations in neurodegeneration. Biochim. Biophys. Acta 1847, 1401–1411 (2015).
Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003).
Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).
Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).
Fivenson, E. M. et al. Mitophagy in neurodegeneration and aging. Neurochem. Int. 109, 202–209 (2017).
Koentjoro, B., Park, J. S. & Sue, C. M. Nix restores mitophagy and mitochondrial function to protect against PINK1/parkin-related Parkinson’s disease. Sci. Rep. 7, 44373 (2017).
Di Rita, A. et al. AMBRA1-mediated mitophagy counteracts oxidative stress and apoptosis induced by neurotoxicity in human neuroblastoma SH-SY5Y cells. Front. Cell. Neurosci. 12, 92 (2018).
Yun, J. et al. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. Elife 3, e01958 (2014).
Haynes, C. M. & Ron, D. The mitochondrial UPR – protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).
Kultz, D. Molecular and evolutionary basis of the cellular stress response. Annu. Rev. Physiol. 67, 225–257 (2005).
Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).
Loaiza, N. & Demaria, M. Cellular senescence and tumor promotion: is aging the key? Biochim. Biophys. Acta 1865, 155–167 (2016).
Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).
Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).
Nacarelli, T. et al. NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 21, 397–407 (2019).
Maynard, S., Fang, E. F., Scheibye-Knudsen, M., Croteau, D. L. & Bohr, V. A. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a025130 (2015).
Barrio-Alonso, E., Hernandez-Vivanco, A., Walton, C. C., Perea, G. & Frade, J. M. Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons. Sci. Rep. 8, 14316 (2018).
Fielder, E., von Zglinicki, T. & Jurk, D. The DNA damage response in neurons: die by apoptosis or survive in a senescence-like state? J. Alzheimers Dis. 60, S107–S131 (2017).
Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012).
Vaidya, A. et al. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age. PLoS Genet. 10, e1004511 (2014).
Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).
Gewirtz, D. A. Autophagy and senescence: a partnership in search of definition. Autophagy 9, 808–812 (2013).
Kang, H. T., Lee, K. B., Kim, S. Y., Choi, H. R. & Park, S. C. Autophagy impairment induces premature senescence in primary human fibroblasts. PLoS One 6, e23367 (2011).
Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).
Bhatia-Dey, N., Kanherkar, R. R., Stair, S. E., Makarev, E. O. & Csoka, A. B. Cellular senescence as the causal nexus of aging. Front. Genet. 7, 13 (2016).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span – from yeast to humans. Science 328, 321–326 (2010).
Babbar, M. & Sheikh, M. S. Metabolic stress and disorders related to alterations in mitochondrial fission or fusion. Mol. Cell. Pharmacol. 5, 109–133 (2013).
Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014).
Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).
Amor, S. & Woodroofe, M. N. Innate and adaptive immune responses in neurodegeneration and repair. Immunology 141, 287–291 (2014).
He, F. & Balling, R. The role of regulatory T cells in neurodegenerative diseases. Wiley Interdiscip. Rev. Syst. Biol. Med. 5, 153–180 (2013).
Cao, W. & Zheng, H. Peripheral immune system in aging and Alzheimer’s disease. Mol. Neurodegener. 13, 51 (2018).
Giunta, S. Is inflammaging an auto[innate]immunity subclinical syndrome? Immun. Ageing 3, 12 (2006).
Currais, A. Ageing and inflammation – a central role for mitochondria in brain health and disease. Ageing Res. Rev. 21, 30–42 (2015).
Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).
Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).
Cunningham, C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71–90 (2013).
Youm, Y. H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013).
Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 9, 857–865 (2008).
Codolo, G. et al. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375 (2013).
Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399, 263–267 (1999).
Johann, S. et al. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63, 2260–2273 (2015).
Meissner, F., Molawi, K. & Zychlinsky, A. Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis. Proc. Natl Acad. Sci. USA 107, 13046–13050 (2010).
Wang, W. Y., Tan, M. S., Yu, J. T. & Tan, L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann. Transl Med. 3, 136 (2015).
Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).
Uchoa, M. F., Moser, V. A. & Pike, C. J. Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front. Neuroendocrinol. 43, 60–82 (2016).
Grune, T., Jung, T., Merker, K. & Davies, K. J. Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease. Int. J. Biochem. Cell Biol. 36, 2519–2530 (2004).
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).
Baker, D. J. & Petersen, R. C. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J. Clin. Invest. 128, 1208–1216 (2018).
Pan, M. R., Li, K., Lin, S. Y. & Hung, W. C. Connecting the dots: from DNA damage and repair to aging. Int. J. Mol. Sci. 17, 685 (2016).
Frasca, D. & Blomberg, B. B. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17, 7–19 (2016).
Bektas, A., Schurman, S. H., Sen, R. & Ferrucci, L. Aging, inflammation and the environment. Exp. Gerontol. 105, 10–18 (2018).
Valera, E. et al. Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol. Commun. 5, 2 (2017).
Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).
Van Cauwenberghe, C., Vandendriessche, C., Libert, C. & Vandenbroucke, R. E. Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease. Mamm. Genome 27, 300–319 (2016).
Spielman, L. J., Little, J. P. & Klegeris, A. Physical activity and exercise attenuate neuroinflammation in neurological diseases. Brain Res. Bull. 125, 19–29 (2016).
Bekris, L. M., Yu, C. E., Bird, T. D. & Tsuang, D. W. Genetics of Alzheimer disease. J. Geriatr. Psychiatry Neurol. 23, 213–227 (2010).
Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).
Bloom, G. S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–508 (2014).
Wang, J., Gu, B. J., Masters, C. L. & Wang, Y. J. A systemic view of Alzheimer disease – insights from amyloid-β metabolism beyond the brain. Nat. Rev. Neurol. 13, 612–623 (2017).
Lane, C. A., Hardy, J. & Schott, J. M. Alzheimer’s disease. Eur. J. Neurol. 25, 59–70 (2018).
Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).
Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. Lancet Neurol. 12, 609–622 (2013).
Fu, W. Y., Wang, X. & Ip, N. Y. Targeting neuroinflammation as a therapeutic strategy for Alzheimer’s disease: mechanisms, drug candidates, and new opportunities. ACS Chem. Neurosci. 10, 872–879 (2019).
Hardy, J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J. Neurochem. 110, 1129–1134 (2009).
Hall, A. M. & Roberson, E. D. Mouse models of Alzheimer’s disease. Brain Res. Bull. 88, 3–12 (2012).
Ewald, C. Y. & Li, C. Understanding the molecular basis of Alzheimer’s disease using a Caenorhabditis elegans model system. Brain Struct. Funct. 214, 263–283 (2010).
Prussing, K., Voigt, A. & Schulz, J. B. Drosophila melanogaster as a model organism for Alzheimer’s disease. Mol. Neurodegener. 8, 35 (2013).
Tan, F. H. P. & Azzam, G. Drosophila melanogaster: deciphering Alzheimer’s disease. Malays. J. Med. Sci. 24, 6–20 (2017).
Arber, C., Lovejoy, C. & Wray, S. Stem cell models of Alzheimer’s disease: progress and challenges. Alzheimers Res. Ther. 9, 42 (2017).
Teng, E. et al. Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization. Neurobiol. Dis. 82, 552–560 (2015).
Lovell, M. A., Gabbita, S. P. & Markesbery, W. R. Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J. Neurochem. 72, 771–776 (1999).
Weissman, L. et al. Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res. 35, 5545–5555 (2007).
Sykora, P. et al. DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res. 43, 943–959 (2015).
Wang, H. Z. et al. Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations. Mol. Neurobiol. 53, 379–390 (2016).
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).
Hou, Y. et al. NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc. Natl Acad. Sci. USA 115, E1876–E1885 (2018).
Kwon, M. J., Kim, S., Han, M. H. & Lee, S. B. Epigenetic changes in neurodegenerative diseases. Mol. Cells 39, 783–789 (2016).
Ow, S. Y. & Dunstan, D. E. A brief overview of amyloids and Alzheimer’s disease. Protein Sci. 23, 1315–1331 (2014).
Kerr, J. S. et al. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci. 40, 151–166 (2017).
Fang, E. F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).
Bhat, R. et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 7, e45069 (2012).
Boccardi, V., Pelini, L., Ercolani, S., Ruggiero, C. & Mecocci, P. From cellular senescence to Alzheimer’s disease: the role of telomere shortening. Ageing Res. Rev. 22, 1–8 (2015).
Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep 22, 930–940 (2018).
Turnquist, C. et al. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration. Cell Death Differ. 23, 1515–1528 (2016).
He, N. et al. Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis. 4, e924 (2013).
Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).
Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).
Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).
Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).
Talbot, K. et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–1338 (2012).
Oddo, S. The role of mTOR signaling in Alzheimer disease. Front. Biosci. (Schol Ed) 4, 941–952 (2012).
Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. & Hiltunen, M. AMP-activated protein kinase: a potential player in Alzheimer’s disease. J. Neurochem. 118, 460–474 (2011).
Camandola, S. & Mattson, M. P. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 36, 1474–1492 (2017).
De Felice, F. G. & Lourenco, M. V. Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease. Front. Aging Neurosci. 7, 94 (2015).
Cai, H. et al. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Curr. Alzheimer Res. 9, 5–17 (2012).
Simons, M. et al. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc. Natl Acad. Sci. USA 95, 6460–6464 (1998).
Vivar, C. Adult hippocampal neurogenesis, aging and neurodegenerative diseases: possible strategies to prevent cognitive impairment. Curr. Top. Med. Chem. 15, 2175–2192 (2015).
McClean, P. L., Parthsarathy, V., Faivre, E. & Holscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J. Neurosci. 31, 6587–6594 (2011).
Ho, L. et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J. 18, 902–904 (2004).
Takamatsu, Y. et al. Combined immunotherapy with “anti-insulin resistance” therapy as a novel therapeutic strategy against neurodegenerative diseases. NPJ Parkinsons Dis. 3, 4 (2017).
Heneka, M. T., Reyes-Irisarri, E., Hull, M. & Kummer, M. P. Impact and therapeutic potential of PPARs in Alzheimer’s disease. Curr. Neuropharmacol. 9, 643–650 (2011).
Rotermund, C., Machetanz, G. & Fitzgerald, J. C. The therapeutic potential of metformin in neurodegenerative diseases. Front. Endocrinol. 9, 400 (2018).
Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017).
Melki, R. Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases. J. Parkinsons Dis. 5, 217–227 (2015).
Rocha, E. M., De Miranda, B. & Sanders, L. H. Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol. Dis. 109, 249–257 (2018).
Dias, V., Junn, E. & Mouradian, M. M. The role of oxidative stress in Parkinson’s disease. J. Parkinsons Dis. 3, 461–491 (2013).
Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).
Sepe, S. et al. Inefficient DNA repair is an aging-related modifier of Parkinson’s disease. Cell Rep. 15, 1866–1875 (2016).
Labbe, C., Lorenzo-Betancor, O. & Ross, O. A. Epigenetic regulation in Parkinson’s disease. Acta Neuropathol. 132, 515–530 (2016).
Curry, D. W., Stutz, B., Andrews, Z. B. & Elsworth, J. D. Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease. J. Parkinsons Dis. 8, 161–181 (2018).
Alecu, I. & Bennett, S. A. L. Dysregulated lipid metabolism and its role in α-synucleinopathy in Parkinson’s disease. Front. Neurosci. 13, 328 (2019).
Regensburger, M., Prots, I. & Winner, B. Adult hippocampal neurogenesis in Parkinson’s disease: impact on neuronal survival and plasticity. Neural Plast. 2014, 454696 (2014).
Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548, 592–596 (2017).
McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38, 1285–1291 (1988).
McKinnon, P. J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772–776 (2004).
Walter, J. T., Alvina, K., Womack, M. D., Chevez, C. & Khodakhah, K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat. Neurosci. 9, 389–397 (2006).
Valentin-Vega, Y. A. et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119, 1490–1500 (2012).
Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science 330, 517–521 (2010).
Hardiman, O. et al. Amyotrophic lateral sclerosis. Nat. Rev. Dis. Primers 3, 17071 (2017).
Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Primers 1, 15005 (2015).
Karikkineth, A. C., Scheibye-Knudsen, M., Fivenson, E., Croteau, D. L. & Bohr, V. A. Cockayne syndrome: clinical features, model systems and pathways. Ageing Res. Rev. 33, 3–17 (2017).
Penndorf, D., Witte, O. W. & Kretz, A. DNA plasticity and damage in amyotrophic lateral sclerosis. Neural Regen. Res. 13, 173–180 (2018).
Cai, Z., Yan, L. J. & Ratka, A. Telomere shortening and Alzheimer’s disease. Neuromol. Med. 15, 25–48 (2013).
Linkus, B. et al. Telomere shortening leads to earlier age of onset in ALS mice. Aging 8, 382–393 (2016).
Kota, L. N. et al. Reduced telomere length in neurodegenerative disorders may suggest shared biology. J. Neuropsychiatry Clin. Neurosci. 27, e92–e96 (2015).
Block, R. C., Dorsey, E. R., Beck, C. A., Brenna, J. T. & Shoulson, I. Altered cholesterol and fatty acid metabolism in Huntington disease. J. Clin. Lipidol. 4, 17–23 (2010).
Allen, D. M. et al. Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev. 15, 554–566 (2001).
Amariglio, N. et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 6, e1000029 (2009).
Sapp, E. et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J. Neuropathol. Exp. Neurol. 60, 161–172 (2001).
Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004).
Hui, C. W., Song, X., Ma, F., Shen, X. & Herrup, K. Ibuprofen prevents progression of ataxia telangiectasia symptoms in ATM-deficient mice. J. Neuroinflammation 15, 308 (2018).
Chow, H. M. et al. ATM is activated by ATP depletion and modulates mitochondrial function through NRF1. J. Cell Biol. 218, 909–928 (2019).
Chen, J. et al. The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment. Mol. Neurodegener. 11, 60 (2016).
Trammell, S. A. et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 7, 12948 (2016).
Zhang, H. et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).
Gomes, A. P. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).
De Jesus-Cortes, H. et al. Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. Proc. Natl Acad. Sci. USA 109, 17010–17015 (2012).
Phelan, M. J., Mulnard, R. A., Gillen, D. L. & Schreiber, S. S. Phase II clinical trial of nicotinamide for the treatment of mild to moderate Alzheimer’s disease. J. Geriatr. Med. Gerontol. 3, 021 (2017).
Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).
Georgakopoulos, N. D., Wells, G. & Campanella, M. The pharmacological regulation of cellular mitophagy. Nat. Chem. Biol. 13, 136–146 (2017).
Albani, D., Polito, L., Signorini, A. & Forloni, G. Neuroprotective properties of resveratrol in different neurodegenerative disorders. Biofactors 36, 370–376 (2010).
Heilman, J., Andreux, P., Tran, N., Rinsch, C. & Blanco-Bose, W. Safety assessment of urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins andellagic acid. Food Chem. Toxicol. 108, 289–297 (2017).
Moreira, O. C. et al. Mitochondrial function and mitophagy in the elderly: effects of exercise. Oxid. Med. Cell. Longev. 2017, 2012798 (2017).
Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).
Walters, H. E., Deneka-Hannemann, S. & Cox, L. S. Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging 8, 231–244 (2016).
Katila, N. et al. Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology 125, 396–407 (2017).
Ou, Z. et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain. Behav. Immun. 69, 351–363 (2018).
Naylor, R. M., Baker, D. J. & van Deursen, J. M. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. Ther. 93, 105–116 (2013).
Krimpenfort, P. & Berns, A. Rejuvenation by therapeutic elimination of senescent cells. Cell 169, 3–5 (2017).
Chiti, F. & Dobson, C. M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem 86, 27–68 (2017).
Jack, C. R. Jr. et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).
Medina, M. An overview on the clinical development of tau-based therapeutics. Int. J. Mol. Sci. 19, 1160 (2018).
Braak, H. & Braak, E. Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol. Scand. Suppl. 165, 3–12 (1996).
Cummings, J., Lee, G., Ritter, A. & Zhong, K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement. 4, 195–214 (2018).
Cao, B. et al. Comparative efficacy and acceptability of antidiabetic agents for Alzheimer’s disease and mild cognitive impairment: a systematic review and network meta-analysis. Diabetes Obes. Metab. 20, 2467–2471 (2018).
Miguel-Alvarez, M. et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging 32, 139–147 (2015).
Rees, K. et al. Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database of Systematic Reviews 9, CD008454 (2011).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02588677 (2018).
Petrov, D., Mansfield, C., Moussy, A. & Hermine, O. ALS clinical trials review: 20 years of failure. are we any closer to registering a new treatment? Front. Aging Neurosci. 9, 68 (2017).
Vaiserman, A. M., Lushchak, O. V. & Koliada, A. K. Anti-aging pharmacology: promises and pitfalls. Ageing Res. Rev. 31, 9–35 (2016).
Hernandez-Camacho, J. D., Bernier, M., Lopez-Lluch, G. & Navas, P. Coenzyme Q10 supplementation in aging and disease. Front. Physiol. 9, 44 (2018).
Li, T. & Chen, Z. J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).
Giraldez-Perez, R., Antolin-Vallespin, M., Munoz, M. & Sanchez-Capelo, A. Models of α-synuclein aggregation in Parkinson’s disease. Acta Neuropathol. Commun. 2, 176 (2014).
Reitz, C. & Mayeux, R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 88, 640–651 (2014).
Vina, J. & Lloret, A. Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-β peptide. J. Alzheimers Dis. 20, S527–S533 (2010).
Luchsinger, J. A. et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65, 545–551 (2005).
Grant, W. B., Campbell, A., Itzhaki, R. F. & Savory, J. The significance of environmental factors in the etiology of Alzheimer’s disease. J. Alzheimers Dis. 4, 179–189 (2002).
Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).
Weintraub, D. & Stern, M. B. Psychiatric complications in Parkinson disease. Am. J. Geriatr. Psychiatry 13, 844–851 (2005).
Mak, E. et al. Cognitive deficits in mild Parkinson’s disease are associated with distinct areas of grey matter atrophy. J. Neurol. Neurosurg. Psychiatry 85, 576–580 (2014).
Talbott, E. O., Malek, A. M. & Lacomis, D. The epidemiology of amyotrophic lateral sclerosis. Handb. Clin. Neurol. 138, 225–238 (2016).
Walker, F. O. Huntington’s disease. Lancet 369, 218–228 (2007).
Subramaniam, S., Sixt, K. M., Barrow, R. & Snyder, S. H. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327–1330 (2009).
Duff, K. et al. Psychiatric symptoms in Huntington’s disease before diagnosis: the Predict-HD study. Biol. Psychiatry 62, 1341–1346 (2007).
Zweig, Y. R. & Galvin, J. E. Lewy body dementia: the impact on patients and caregivers. Alzheimers Res. Ther. 6, 21 (2014).
Rothblum-Oviatt, C. et al. Ataxia telangiectasia: a review. Orphanet J. Rare Dis. 11, 159 (2016).
Kleijer, W. J. et al. Incidence of DNA repair deficiency disorders in western Europe: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair 7, 744–750 (2008).
The authors’ research is supported by the Intramural Research Program of the NIH National Institute on Aging. The authors thank B. Yang and N. B. Fakouri for critical reading of the manuscript. The Bohr laboratory receives nicotinamide riboside as a gift from ChromaDex.
The authors declare no competing interests.
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Hou, Y., Dan, X., Babbar, M. et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15, 565–581 (2019). https://doi.org/10.1038/s41582-019-0244-7
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