Advances in pharmacological interventions of aging in mice

Translational Medicine of Aging 3 (2019) 116e120

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Advances in pharmacological interventions of aging in mice Minxian Qian a, b, c, Baohua Liu a, b, c, * a

Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, 518055, China Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, 518055, China c National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University, Shenzhen, 518055, China b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 August 2019 Received in revised form 24 October 2019 Accepted 1 November 2019 Available online 11 November 2019

The remarkable breakthroughs in aging research pave the way allowing us to explore potential interventions to slow down aging process, and more importantly, to improve healthiness. Multiple approaches, including pharmacological and non-pharmacological interventions (e.g. caloric restriction, physical exercise), to a great extent, successfully tackle challenges of age-related phenotypic deficits across species. To date, molecular compounds are largely emerging, such as caloric restriction mimetics, NADþ boosters, and senolytics. The use of mouse models is essential, as one of the best tools, to evaluate the potentials of molecules against aging and to provide a translational basis for treating human frailty. Here, we briefly overview present advances on therapeutic interventions against aging in laboratory mouse models and discuss the benefits and pitfalls on their clinical application for anti-aging and agingrelated pathologies in humans. © 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communication Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Keywords: Pharmacological intervention of aging Mouse model

1. Introduction Aging is characterized by the progressive but inevitable deterioration of physiological function and a high-risk factor leading to the development of all major life-threatening diseases, such as type 2 diabetes, heart diseases, cancer and neurodegenerative diseases. Human aging brings tremendous social, medical and economic burdens for all countries around the world. Developing efficacious intervention approaches to ensure healthy aging is apparently meaningful and urgent [1e3]. Based on the profound benefits of caloric restriction (CR), one best-studied lifestyle to improve quality lifespan in most organisms, an increasing number of fasting-mimetic meals and compounds mimicking the action of CR have been identified. CR counteracts aging process by regulating a set of evolutionarily conserved pathways, including the kinase target of rapamycin (TOR), AMP-activated protein kinase (AMPK), sirtuins and insulin/ insulin-like growth factor (IGF-1) [4e6]. Recently, nicotinamide adenine dinucleotide (NADþ), which declines with age and benefits against aging and age-related diseases, attracts more and more

* Corresponding author. Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Medical Research Center, Shenzhen University, Shenzhen, 518060, China. E-mail address: [email protected] (B. Liu).

researchers to design the compounds bolstering cellular NADþ levels [7,8]. New preclinical compounds, called seneolytics, selectively clear up senescent cells in vivo and extend lifespan and healthspan across species, rapidly spring up since the concept was first proposed in 2011 [9,10] Fig. 1. Model organisms have been widely employed not only to discover the conserved aging pathways, but also to evaluate interventions to improve both longevity and healthspan, and the applicability against human aging. Laboratory mouse and rat with clear genetic background, short lifespan, convenience of feeding, established genetic manipulation and response capacity to environmental risks are commonly used in aging research field [11]. Knockout mouse models have been generated, recapitulating aging features in inherited human diseases, including Werner syndrome, Hutchinson-Gilford progeria syndrome (HGPS), Ataxia telangiectasia and Cockayne syndrome. These mouse models provide many advantages for research on aging mechanisms and interventions. Here, we summarize current knowledge on pharmaceutical interventions of mouse aging and discuss the challenges that lie ahead for clinical trials. 1.1. Rapamycin targeting mTORC1 signaling Low mTORC1 activity contributes to exceptional longevity and enhanced healthspan across species. Rapamycin, which blocks the

https://doi.org/10.1016/j.tma.2019.11.002 2468-5011/© 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communication Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Fig. 1. Pharmacological interventions and targeted pathways of aging.

interaction between mTOR and raptor, is first indicated to slow mammalian aging. Long-term treatment with rapamycin from 6 months of age significantly increased (10%e18%) the mean lifespan of mice [12]. Transient rapamycin treatment prolongs ovarian lifespan in both young and middle-aged female mice [13]. Rapamycin could prolong the lifespan by 50% in a premature aging mouse model of Baml1 deficiency, a core clock gene [14], but not in the mice with genetically enhanced NF-kB activity (Nfkb1/) [15]. Moreover, rapamycin treatment could maintain cognitive function [16] and enhance mitochondrial DNA quality in aged mice [17]. By contrast, rapamycin treatment impairs longevity of growth hormone receptor (Ghr) knockout (KO) mice, which have suppressed mTORC1 but upregulated mTORC2 signaling [18]. This seemingly discordance is likely owing to the drastic reduction of mTORC2 and disruption of whole-body homeostasis. Intriguingly, rapamycin treatment could inhibit wound healing, probably resulted from its immunosuppressive properties [19,20]. More thorough assessments on rapamycin are required before application for human aging. 1.2. Metformin activating AMPK signaling Metformin is prescribed for anti-diabetes [21e23]. It regulates global DNA methylation to promote metabolic reprogramming [24]. Long-term treatment with metformin improves the healthspan and lifespan in mice, by increasing AMPK kinase activity [25]. Metformin also delays murine ovarian aging [26] and reduces neuronal dysfunction in mouse models of Huntington’s disease (HD) [27]. Interestingly, Anisimov et al. found that metformin only slightly increases the mean lifespan of female mice but decreased that of male mice [28]. In another study, metformin alone doesn’t extend lifespan, but robustly extends lifespan when combined with rapamycin [29]. Nonetheless, metformin exhibits promising effects on life-extending and health-promoting, and its clinical potential. 1.3. Spermidine targeting autophagy activation Autophagic rates decline with age in most organisms [30], as a

potential mechanism underlying many age-related pathologies, like Parkinson’s and Alzheimer’s diseases [31,32]. The natural polyamine spermidine extends lifespan of mice and exerts cardioprotective effects in old mice via autophagy activation [33]. Indeed, polyamine synthesis decreases with aging. Boosting spermidine level by spermidine intake or gut bacteria-produced polyamine is capable of lifespan promotion in short-lived mouse models [34,35]. Life extension of up to 25% can be produced by lifelong administration of spermidine, accompanied by reduced liver fibrosis and hepatocellular carcinoma [36]. Spermidine induces neuronal autophagy and impedes a number of neurological pathologies, by inducing autophagy [37]. In Addition, spermidine activates casein kinase 2 (CK2), ameliorates aging features and extends lifespan in a mouse model of HGPS [38]. 1.4. Sirtuin activators Resveratrol, as a SIRT1 activator, extends lifespan of mice fed a high-fat diet [39], but has little effect on mean or maximum lifespan of mice fed a normal diet [39,40]. Resveratrol improves osteoblast activity and bone formation [41,42]. On the other side, resveratrol could extend healthspan in aging rodents [39,43,44]. Resveratrol treatment seems safe and well-tolerated in a phase II clinical trial, and attenuates cognitive decline in patients with Alzheimer disease [45]. Contrastingly, in another clinical trial, daily oral supplementation of resveratrol exhibits no improvement in patients with metabolic syndrome [46]. Worse more, resveratrol at high concentration rather represses antigen receptor signaling and arrests cell cycle in human CD4þ T cells [47]. SRT1720, a more potent SIRT1 activator than resveratrol, extends lifespan and improves healthspan of adult mice fed a high-fat diet or a standard diet [48e50]. Moreover, SRT1720 enhances insulin sensitivity, improves bone mass, and inhibits tumor growth [51e53]. Likewise, SRT2104, a first-in-class and highly selective activator of SIRT1, extends the mean and maximal lifespan in mice fed a normal diet, accompanied with improved whole-body physiology [54]. MDL800 was most recently discovered as a first-in-class small-

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molecule cellular SIRT6 activator [55]. Considering the wellestablished pro-longevity role of SIRT6, we believe that the benefits of MDL-800 on anti-aging would be largely evaluated in rodents. 1.5. Co-enzyme NADþ boosters NADþ boosters, including NADþ precursors, NADþ synthesis enhancers and inhibitors of NADþ-consuming enzymes, have been largely discovered able to extend lifespan and improve healthspan in normal and premature aging model organisms, like nicotinamide (NAM/vitamin B3), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). A decline of NADþ level has been shown in elder mice or premature aging animal models [56,57]. Administration of NR rejuvenates intestinal stem cells in old mice [58] and increases lifespan (~5%) [59]. Elena et al. showed pharmacological inhibition of ACMSD, a key modulator of cellular NADþ synthesis, improves mitochondrial homeostasis and health outcomes in nematodes and mice [60]. Supplementing eNAMPT (a rate-limiting synthase in NADþ salvage)-containing extracellular vesicles isolated from young mice extends lifespan in aged mice [61]. NADþ replenishment also improves both lifespan and healthspan in premature aging mouse models caused by deficient DNA repair machinery, e.g. NR administration extends lifespan of Atme/e mice [62] and NMN treatment increases the lifespan of BubR1 (a mitotic checkpoint kinase) null mice [63]. Intriguingly, Sarash et al. pointed out that NAM improves aspects of healthspan but not lifespan in mice fed a standard diet or HFD [64]. Indeed, NADþ (precursor) supplementation indicates a wide range of beneficial effects as reported, such as improving glucose homeostasis [65], maintaining genomic integrity [56], restoring muscle mass [66], preventing heart failure [67], steatosis [68] and glaucoma [69] in aged mice. Of note, NR is approved orally available and safe to increase the blood NADþ metabolism in mice and humans [70]. Thus, NADþ boosters are highly considered as the promising therapeutic drugs to slow aging and improve the quality of life in humans. 1.6. Senolytics eliminating senescent cells A group of senolytics is characterized to selectively remove senescent cells in vivo. The idea was first proposed to promote longevity and healthiness in 2011 [9]. Accumulation of senescent cells with age causes the onset of tissue deterioration and diseases. Treatment with senolytic cocktail, dasatinib plus quercetin, is sufficient to alleviate a wide range of age-related features in mice [71], to restore neurogenesis in high fat-fed or leptin receptor-deficient obese mice [72] and to extend lifespan in aged mice [73]. The benefits to eliminate senescent cells are further supported by senolytic AP20187, which extends the median lifespan of mice by about 25% [74] and prevents age-driven bone loss [75]. Senolytic compound navitoclax has been addressed to ameliorate cognitive deficits in mice with Alzheimer’s disease [76] and a mouse model of tau-dependent neurodegenerative disease [77]. Although many investigators propagate optimistic views on the lifespan-extending advantages of senolytics, even on clinical use for anti-aging treatment in humans, the safety and efficacy of these drugs should be carefully and fully evaluated in different laboratory animals. 2. Conclusion Pharmacological intervention of aging is becoming flourishing. An increasing number of small molecules has emerged to prolong lifespan and/or sustain health late in life in short-lived experimental animals, from yeast to vertebrates. Mouse models stand out as a good tool to uncover the mechanism of mammalian aging and

appraise the therapeutic effects on aging and age-related diseases. In addition to the molecules described above, there are some other pharmacological agents, such as chloroquine [57], glycine [78] and acarbose [79], offering more potential therapeutic drugs against aging in mice. Aging is rather complicated. Many basic questions on anti-aging drugs merit thoughtful consideration before translating to humans. For example, how does these interventions precisely postpone aging process? Could these interventions be validated in different organisms? Are these interventions safe and applicable for humans? To achieve healthy aging, the druggable molecular targets should be well-designed using diverse laboratory model systems to assessment and validation [3,80]. Though clinical application with some compounds has been shown to benefit healthy life in older individuals, barriers couldn’t be ignored. The quantification of human aging and the period for human test make clinical trials on humans unrealistic [81]. The safety and bioavailability of long-term interventions should be comprehensively assessed before running trials on humans [82]. Declaration of competing interest The authors declare no conflict of interest. Acknowledgements This work was supported by National Natural Science Foundation of China (81571374, 91849208, 81871114, 81972602 and 81702909), National Key R&D Program of China (2017YFA0503900), Guangdong Province National Natural Science Foundation (2014A030308011 and 2015A030308007), Shenzhen government (JCYJ20160226 191451487 and KQJSCX20180328093403969). References [1] J. Butler, A. Kalogeropoulos, V. Georgiopoulou, R. Belue, N. Rodondi, M. Garcia, D.C. Bauer, S. Satterfield, A.L. Smith, V. Vaccarino, et al., Incident heart failure prediction in the elderly: the health ABC heart failure score, Circ. Heart Fail. 1 (2008) 125e133. [2] S.J. Olshansky, Commentary: prescient visions of public health from Cornaro to Breslow, Int. J. Epidemiol. 35 (2006) 22e23. [3] M. Qian, B. Liu, Pharmaceutical intervention of aging, Adv. Exp. Med. Biol. 1086 (2018) 235e254. [4] P. Balasubramanian, P.R. Howell, R.M. Anderson, Aging and caloric restriction research: a biological perspective with translational potential, EBioMedicine 21 (2017) 37e44. [5] L. Fontana, S. Klein, J.O. Holloszy, Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production, Age 32 (2010) 97e108. [6] F. Madeo, D. Carmona-Gutierrez, S.J. Hofer, G. Kroemer, Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential, Cell Metabol. 29 (2019) 592e610. [7] M.S. Bonkowski, D.A. Sinclair, Slowing ageing by design: the rise of NAD(þ) and sirtuin-activating compounds, Nat. Rev. Mol. Cell Biol. 17 (2016) 679e690. [8] E.F. Fang, S. Lautrup, Y. Hou, T.G. Demarest, D.L. Croteau, M.P. Mattson, V.A. Bohr, NAD(þ) in aging: molecular mechanisms and translational implications, Trends Mol. Med. 23 (2017) 899e916. [9] D.J. Baker, T. Wijshake, T. Tchkonia, N.K. LeBrasseur, B.G. Childs, B. van de Sluis, J.L. Kirkland, J.M. van Deursen, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature 479 (2011) 232e236. [10] J.L. Kirkland, T. Tchkonia, Cellular senescence: a translational perspective, EBioMedicine 21 (2017) 21e28. [11] S.J. Mitchell, M. Scheibye-Knudsen, D.L. Longo, R. de Cabo, Animal models of aging research: implications for human aging and age-related diseases, Annu. Rev. Anim. Biosci. 3 (2015) 283e303. [12] R.A. Miller, D.E. Harrison, C.M. Astle, J.A. Baur, A.R. Boyd, R. de Cabo, E. Fernandez, K. Flurkey, M.A. Javors, J.F. Nelson, et al., Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice, J. Gerontol.Ser A. 66 (2011) 191e201. Biological sciences and medical sciences. [13] X. Dou, Y. Sun, J. Li, J. Zhang, D. Hao, W. Liu, R. Wu, F. Kong, X. Peng, J. Li, Shortterm rapamycin treatment increases ovarian lifespan in young and middleaged female mice, Aging Cell 16 (2017) 825e836.

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