Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N.Y. Acad. Sci. 908, 244–254 (2000).
Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).
Smith, L. K. et al. beta2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat. Med. 21, 932–937 (2015).
Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).
Rebo, J. et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7, 13363 (2016).
Ruckh, J. M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell. Stem. Cell. 10, 96–103 (2012).
Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).
Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).
Li, H., Qi, Y. & Jasper, H. Preventing age-related decline of gut compartmentalization limits microbiota dysbiosis and extends lifespan. Cell. Host. Microbe 19, 240–253 (2016).
Clark, R. I. & Walker, D. W. Role of gut microbiota in aging-related health decline: insights from invertebrate models. Cell. Mol. Life Sci. 75, 93–101 (2017).
Clark, R. I., Walker, D. W. & Dionne, M. S. Metabolic and immune integration in aging and age-related disease. Aging 6, 3–4 (2014).
Barzilai, N., Huffman, D. M., Muzumdar, R. H. & Bartke, A. The critical role of metabolic pathways in aging. Diabetes 61, 1315–1322 (2012).
Gan, L., Chitturi, S. & Farrell, G. C. Mechanisms and implications of age-related changes in the liver: nonalcoholic fatty liver disease in the elderly. Curr. Gerontol. Geriatr. Res. 2011, 831536 (2011).
Sheedfar, F., Di Biase, S., Koonen, D. & Vinciguerra, M. Liver diseases and aging: friends or foes? Aging Cell. 12, 950–954 (2013).
Park, J. H. et al. Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice. Aging Cell. 13, 709–718 (2014).
Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Eng. J. Med. 356, 1517–1526 (2007).
Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).
Neves, J. et al. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science 353, aaf3646 (2016).
Lindholm, P. & Saarma, M. Novel CDNF/MANF family of neurotrophic factors. Dev. Neurobiol. 70, 360–371 (2010).
Galli, E. et al. Increased circulating concentrations of mesencephalic astrocyte-derived neurotrophic factor in children with type 1 diabetes. Sci. Rep. 6, 29058 (2016).
Wu, T. et al. Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance. Endocr. J. 64, 403–410 (2017).
Lindholm, P. et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol. Cell. Neurosci. 39, 356–371 (2008).
Lindahl, M., Saarma, M. & Lindholm, P. Unconventional neurotrophic factors CDNF and MANF: structure, physiological functions and therapeutic potential. Neurobiol. Dis. 97, 90–102 (2017).
Voutilainen, M. H. et al. Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson’s disease. J. Neurosci. 29, 9651–9659 (2009).
Chen, L. et al. Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-kappaB pathway. Sci. Rep. 5, 8133 (2015).
Yang, S., Huang, S., Gaertig, M. A., Li, X. J. & Li, S. Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron 81, 349–365 (2014).
Glass, D. et al. Gene expression changes with age in skin, adipose tissue, blood and brain. Genome Biol. 14, R75 (2013).
Ayyaz, A. & Jasper, H. Intestinal inflammation and stem cell homeostasis in aging Drosophila melanogaster. Front. Cell. Infect. Microbiol. 3, 98 (2013).
Yang, S. et al. MANF regulates hypothalamic control of food intake and body weight. Nat. Commun. 8, 579 (2017).
Lindahl, M. et al. MANF is indispensable for the proliferation and survival of pancreatic beta cells. Cell Rep. 7, 366–375 (2014).
Schmucker, D. L. Age-related changes in liver structure and function: implications for disease? Exp. Gerontol. 40, 650–659 (2005).
Rabinowitz, S. S. & Gordon, S. Macrosialin, a macrophage-restricted membrane sialoprotein differentially glycosylated in response to inflammatory stimuli. J. Exp. Med. 174, 827–836 (1991).
Kinoshita, M. et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J. Hepatol. 53, 903–910 (2010).
Walker, D. G. & Lue, L. F. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res. Ther. 7, 56 (2015).
Oishi, Y. & Manabe, I. Macrophages in age-related chronic inflammatory diseases. N.P.J. Aging Mech. Dis. 2, 16018 (2016).
Baker, D. J. et al. Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Higami, Y. et al. Aging accelerates but life-long dietary restriction suppresses apoptosis-related Fas expression on hepatocytes. Am. J. Pathol. 151, 659–663 (1997).
Gregg, S. Q. et al. A mouse model of accelerated liver aging caused by a defect in DNA repair. Hepatology 55, 609–621 (2012).
Le Couteur, D. G., et al. in Calorie Restriction, Aging and Longevity (eds Everitt, A., Rattan, S., le Couteur, D. & de Cabo, R.) Ch. 11 (Springer, Dordrecht, 2010).
Yang, L., Yang, L., Dong, C. & Li, L. The class D scavenger receptor CD68 contributes to mouse chronic liver injury. Immunol. Res. 66, 414–424 (2018).
Stahl, E. C. & Brown, B. N. Kupffer cell subsets differ between young and aged murine livers. J. Immunol. 196(1 Supplement), 126.131 (2016).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Singh, P. et al. Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47, 1680–1690 (2008).
White, R. R. et al. Comprehensive transcriptional landscape of aging mouse liver. BMC Genom. 16, 899 (2015).
Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).
Warren, A. et al. The effects of old age on hepatic stellate cells. Curr. Gerontol. Geriatr. Res. 2011, 439835 (2011).
Palgi, M., Greco, D., Lindstrom, R., Auvinen, P. & Heino, T. I. Gene expression analysis of Drosophila Manf mutants reveals perturbations in membrane traffic and major metabolic changes. BMC Genom. 13, 134 (2012).
Heckmann, B. L., Zhang, X., Xie, X. & Liu, J. The G0/G1 switch gene 2 (G0S2): regulating metabolism and beyond. Biochim. Biophys. Acta 1831, 276–281 (2013).
Yang, X. et al. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell. Metab. 11, 194–205 (2010).
Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).
Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).
Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017).
Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170, 664–677 e611 (2017).
Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
Swindell, W. R. Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genom. 10, 585 (2009).
Houtkooper, R. H. et al. The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011).
Elabd, C. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082 (2014).
Loffredo, F. S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).
Zhang, G. et al. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature 497, 211–216 (2013).
Neves, J., Sousa-Victor, P. & Jasper, H. Rejuvenating strategies for stem cell-based therapies in aging. Cell. Stem. Cell. 20, 161–175 (2017).
Malhi, H. & Kaufman, R. J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 54, 795–809 (2011).
Wang, Y. et al. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS ONE 8, e72315 (2013).
Sugaya, Y. & Satoh, H. Liver-specific G0 /G1 switch gene 2 (G0s2) expression promotes hepatic insulin resistance by exacerbating hepatic steatosis in male Wistar rats. J. Diabetes 9, 754–763 (2017).
Heckmann, B. L. et al. Liver X receptor alpha mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression. JCI Insight 2, e88735 (2017).
Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).
Day, C. P. Pathogenesis of steatohepatitis. Best practice & research. Clin. Gastroenterol. 16, 663–678 (2002).
Fontana, L. et al. Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. Hepatology 57, 995–1004 (2013).
Yavarna, T. et al. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum. Genet. 134, 967–980 (2015).
Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
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).
Sun, Z. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934–942 (2012).
Liu, F., Song, Y. & Liu, D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther. 6, 1258–1266 (1999).
Tiscornia, G., Singer, O. & Verma, I. M. Production and purification of lentiviral vectors. Nat. Protoc. 1, 241–245 (2006).
Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).