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Turning Back Time with Emerging Rejuvenation Strategies

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Turning Back Time with Emerging Rejuvenation Strategies REVIEW ARTICLE | FOCUS https://doi.org/10.1038/s41556-018-0206-0REVIEW ARTICLE | FOCUS https://doi.org/10.1038/s41556-018-0206-0 Turning back time with emerging rejuvenation strategies Salah Mahmoudi1,4, Lucy Xu1,2,4 and Anne Brunet 1,3* Ageing is associated with the functional decline of all tissues and a striking increase in many diseases. Although ageing has long been considered a one-way street, strategies to delay and potentially even reverse the ageing process have recently been developed. Here, we review four emerging rejuvenation strategies—systemic factors, metabolic manipulations, senescent cell ablation and cellular reprogramming—and discuss their mechanisms of action, cellular targets, potential trade-offs and appli- cation to human ageing. geing represents a major risk factor for many chronic con- to enhance muscle, liver, brain and heart function of aged mice17–24, ditions, including cardiovascular disease, diabetes, cancer, by boosting the function of both stem and differentiated cells17–23. arthritis and frailty1,2. Once considered irreversible, ageing is Sharing blood circulation with a young mouse also reduces genomic A 20 in fact remarkably malleable. Indeed, inhibition of high-nutrient- instability in the aged mouse and reverses age-associated gene sensing pathways (for example, the insulin–insulin-like growth expression signatures25. Blood factors, rather than blood cells, seem factor (IGF) and mechanistic target of rapamycin (mTOR) path- to play a major role in these rejuvenating effects24–26: direct injection ways) and activation of low-nutrient-sensing proteins (for example, of young blood plasma (devoid of cells)25 or of human umbilical 5′ AMP-activated protein kinase (AMPK) and sirtuins) extend lifes- cord plasma (also devoid of cells)26 into aged mice can recapitulate pan in various model organisms3,4. Diet-based interventions, such several aspects of heterochronic parabiosis, notably the increase in as dietary restriction, and pharmacological interventions, includ- neurogenesis and improvement of cognitive functions25,26 (Table 1 ing the mTOR inhibitor rapamycin, improve aspects of ageing even and Supplementary Table 1). These observations raise the possibil- when administered late in life5–10. A key question is whether age- ity that blood factors (for example, proteins, metabolites, lipids and ing of cells, tissues and organisms can be reversed or ‘rejuvenated’ exosomes) could be used to reverse aspects of the ageing process, rather than simply delayed. perhaps even in humans. A host of age-associated features have been identified, with a How does young blood revitalize aged organs and tissues? Young subset being potential drivers of the ageing process (extensively blood may contain pro-rejuvenation factors, or it could dilute or reviewed elsewhere1,2). At the molecular level, ageing hallmarks inhibit pro-ageing factors in aged blood (Fig. 2). The pro-rejuve- comprise DNA damage, epigenetic alterations, telomere attrition, nation effect of young blood on the liver, muscle and brain is less protein aggregation and accumulation of aberrant mitochondria pronounced than the pro-ageing effect of aged blood on these tis- and lysosomes1,2. At the cellular and organismal level, ageing features sues27, suggesting the presence of potent pro-ageing factors in aged include cellular senescence, stem cell exhaustion, deregulated nutri- blood. Indeed, systemic pro-ageing factors have been identified ent sensing and chronic low-grade inflammation1,2. Various rejuve- through heterochronic parabiosis, including eotaxin (also known 21 23 nation strategies that target these hallmarks have recently emerged as CCL11) and β 2-microglobulin . The levels of eotaxin and and they fall into four broad categories: systemic (blood) factors, β2 -microglobulin increase with age, and these factors inhibit neu- metabolic manipulations, senescent cell ablation and cellular repro- rogenesis and cognition in young mice21,23. Whether blocking pro- gramming. Although these approaches seemingly target very dif- ageing blood factors improves tissue function in aged mice remains 11–15 ferent ageing features , a central question is whether they share to be shown, but aged β2 -microglobulin knockout mice exhibit common mechanisms of action. This Review discusses these four enhanced neurogenesis and cognitive functions compared to age- rejuvenation strategies and how they improve health and lifespan. matched wild-type mice21,23. Other systemic signalling pathways We also address several key questions: which hallmarks of ageing have been implicated in mediating the pro-ageing effect of aged are targeted by each strategy and are there commonalities in their blood16,17,28–31. For example, heterochronic parabiosis reverses the modes of action? Does the rejuvenating effect come with trade-offs? excessive Wnt signalling underlying the differentiation bias of aged Ultimately, can rejuvenation strategies be used to improve human muscle stem cells16,29. Furthermore, systemic attenuation of trans- health and longevity and target age-associated diseases? forming growth factor-β signalling improves age-dependent decline in neurogenesis and myogenesis30, and inhibition of interferon sig- Blood factors as targets for rejuvenation nalling partially ameliorates neurogenesis and cognitive function in Heterochronic parabiosis studies, in which the circulatory systems aged mice31. Thus, several pro-ageing factors have been identified of a young mouse and an aged mouse are fused, have provided com- in aged blood. pelling evidence that blood factors influence organismal ageing Identifying rejuvenation factors in young blood has been more (Fig. 1, Table 1 and Supplementary Table 1). Heterochronic para- difficult. Heterochronic parabiosis can restore the decreased Notch biosis was initially shown to revitalize muscle stem cells in naturally signalling that underlies the decline in muscle stem cell activation and aged mice, reversing the age-dependent decline in stem cell acti- number17,28, although the specific systemic factor (or factors) remains vation and number and improving their age-associated differentia- unclear. Growth/differentiation factor 11 (GDF11) was initially tion bias16,17. Since then, heterochronic parabiosis has been shown identified as a circulating factor whose levels decrease with age but 1Department of Genetics, Stanford University, Stanford, CA, USA. 2Department of Biology, Stanford University, Stanford, CA, USA. 3Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA, USA. 4These authors contributed equally: Salah Mahmoudi, Lucy Xu. *e-mail: [email protected] 32 NatURE CELL BIOLOGY | VOL 21 | JANUARY 2019 | 32–43 | www.nature.com/naturecellbiology FOCUS | REVIEW ARTICLE NATURE CELL BIOLOGY FOCUShttps://doi.org/10.1038/s41556-018-0206-0 | REVIEW ARTICLE Blood factors Metabolic manipulation Ablation of senescent cells Cellular reprogramming (parabiosis and blood factors) (diet regimens and dietary (genetic ablation or senolytic drugs) (partial reprogramming) restriction mimetics) *Vasculature Vasculature Brain Liver *Brain Liver (neurogenesis, (neurogenesis Liver Kidney Kidney Pancreas cognition and *Metabolism and cognition) Fat tissue remyelination) Cartilage Bone Bone Bone (WT mice) Rejuvenation *Blood Blood Muscle Heart Muscle *Heart Muscle Heart Muscle Median lifespan NT Median lifespan ✓ Median lifespan ✓ Median lifespan NT WT Maximum lifespan NT Maximum lifespan ✓ Maximum lifespan Maximum lifespan NT Median lifespan NT Median lifespan ✓ Median lifespan ✓ Median lifespan ✓ Lifespan Maximum lifespan NT Maximum lifespan Maximum lifespan Maximum lifespan extension ✓ ✓ ✓ Model: Lmna–/– progeroid mice Model: BubR1 progeroid mice Model: LmnaG608G progeroid mice Premature ageing models Inhibition of Elimination of senescent cells Epigenomic remodelling? Blood factors mTOR mTOR pathways Blood factors? action Mode of Autophagy? Stem cell exhausion? Tissue repair impairment Tissue-repair impairment Tumorigenesis Immune response impairment Tissue-specific fibrosis? Tissue dysfunction from (to infections) loss of cellular identity? Haematopoietic system toxicity Increased risk for amenorrhoea Potential trade-offs and osteoporosis upon Gastrointestinal tract toxicity prolonged/severe diet regimens + + + + + + + + Human umbilical plasma reverts Fasting-mimicking diet improves Senolytics eliminate human Cellular reprogramming erases features of ageing in aged mice body weight, blood pressure, senescent cells in vitro age-associated features cholesterol and IGF1 levels and in human cells in vitro In clinical trial TIMP2 enriched in human other physiological readouts umbilical plasma when applied in humans potential Eotaxin and -microglobulin levels ranslational β 2 Rapamycin and metformin improve T increase with age in human plasma risk factors associated with cancer, diabetes and cardiovascular disease In clinical trial In clinical trial Fig. 1 | Comparison of emerging strategies for organismal rejuvenation and lifespan. A comparison of the four emerging rejuvenation strategies: blood factors, metabolic manipulation, ablation of senescent cells and cellular reprogramming. The figure depicts the features that improve when treatment in mice is initiated at midlife or later. The top panel shows organs or tissues that exhibit a rejuvenated phenotype in wild-type (WT) mice. For rapamycin, features that have been shown to improve also in young mice following treatment are indicated with an asterisk (*). The effect on
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