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The road ahead for health and lifespan interventions

lifespan healthspan aging “anti-aging” longevity frailty translation

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#1 Engadin

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Posted 08 March 2020 - 09:23 PM







F U L L   A C C E S S   S O U R C E :   Science Direct






  •  Translation of the advances made from model organisms to human clinical trials still remains a challenge, due to the high heterogeneity in the responses to the different anti-aging interventions (drugs, exercise, diet). How these interventions increase lifespan and improve healthspan in humans by targeting the hallmarks of aging is still unknown.
  •  Successful assessment in the efficacy of an intervention that delays aging will require validation through stringent outcome measures of phenotypic enhancement of longevity in various biological systems.
  •  Using ClinicalTrials.gov, a database of privately and publicly funded clinical studies conducted around the world, we found that exercise, fasting and CR are the interventions with the highest number of clinical trials that target aging as a condition followed by the compounds resveratrol metformin and NAD precursors.
Aging is a modifiable risk factor for most chronic diseases and an inevitable process in humans. The development of pharmacological interventions aimed at delaying or preventing the onset of chronic conditions and other age-related diseases has been at the forefront of the aging field. Preclinical findings have demonstrated that species, sex and strain confer significant heterogeneity on reaching the desired health- and lifespan-promoting pharmacological responses in model organisms. Translating the safety and efficacy of these interventions to humans and the lack of reliable biomarkers that serve as predictors of health outcomes remain a challenge. Here, we will survey current pharmacological interventions that promote lifespan extension and/or increased healthspan in animals and humans, and review the various anti-aging interventions selected for inclusion in the NIA’s Interventions Testing Program as well as the ClinicalTrials.gov database that target aging or age-related diseases in humans.



1. Introduction
Aging has been recognized as a risk factor for most chronic diseases. It is an inevitable progression towards dysfunction and ultimately death across most living organisms, especially mammals. With aging, there is accumulation of damage that leads to an increase in disease vulnerability and death. However, despite years of intense research, the exact underlying mechanisms that govern aging processes remain poorly understood. Why and how we age still remains a mystery.
Most chronic diseases are multifactorial, polygenic and their clinical manifestations tend to emerge late in life (Fabbri et al., 2015; Ferrucci et al., 2018). The recent increase in life expectancy and the decline in birthrates account for the sharp rise in the number and proportion of older adults around the globe. In 2014, people 65 and older represented 14.5 % of the population, but by 2060, the number of elderly persons will double and outpace the number of children under age 5 (World Health Organization, 2015), which will cause a significant burden of age-related diseases on the economy in both developed and developing countries. This demographic change is already having an impact in individual healthcare costs, which will soon surpass 400$ billion dollars per year in the U.S. alone. In order to contain the escalating increase in health care spending, we must reduce the overall burden of disability and chronic disease.
Aging has long been considered a stochastic, inevitable process towards dyfunction and ultimately death (Hayflick, 2000). However, recent advances in the field of gerontology are showing that there are deterministic mechanisms that might be driving aging with some people aging at a slower rate than others. Therefore, aging should be viewed as adaptive and amenable to interventions aimed at extending health span and life span. Individuals with exceptional longevity often have delayed onset of age-related diseases and disabilities (Evert et al., 2003; Lipton et al., 2010), with a compression of morbidity and increased lifespan, living longer and healthier lives. Exceptional longevity and successful aging are only 20 % heritable (Murabito et al., 2012), while some of the main age-related chronic diseases, such as cancer (∼33 %) (Mucci et al., 2016), cardiovascular diseases (∼25-35 %) (Gluckman et al., 2016), dementia (i.e: Alzheimer’s Disease ∼70-79 %) (Selkoe, 1996; Barber, 2012) and others, are highly heritable (Zenin et al., 2019). External factors including environment, psychosocial impact, nutrition, and physical fitness all contribute to deterministic mechanisms of slower/faster aging (Shiels et al., 2019). As we age, our diminished ability to respond to stress renders us more susceptible to adverse health outcomes, leading to declining health and ultimately death. Rockwood and Mitnitski (2011) proposed that this increase in deficit accumulation could represent another way to define frailty.
Ferrucci and colleagues clustered the systemic consequences of the aging process into four main domains (Ferrucci et al., 2010): i) Body composition; ii) balance between energy availability and energy demand; iii) homeostatic dysregulation; and iv) neurodegeneration. Changes in these four domains of the aging phenotypes increase the susceptibility to diseases and reduce the resilience or functional reserve capacity, leading to a condition that is known as frailty and the development of the so-called “geriatric syndromes” (Ferrucci and Studenski, 2012). These syndromes, which include delirium, cognitive impairment, falls, muscle atrophy (e.g. sarcopenia) and disability, are multifactorial and involve systemic changes in many parts of the body with adverse association of comorbidity with mortality. Some of the interventions presented herein target these four domains.
Recently, the landmark review by López-Otín helped conceptualize the hallmarks of aging by grouping of age-associated cellular and molecular mechanisms into three major categories known as ‘primary’, ‘antagonistic’, and ‘integrative’ hallmarks (Lopez-Otin et al., 2013) (Fig. 1). Genomic instability, telomere attrition, epigenetic alteration, and loss of proteostasis are deemed as primary hallmarks, causally related to molecular damage during aging. Antagonistic hallmarks have a beneficial hormetic function and protective role when expressed at low levels, but detrimental effects might occur at high levels. These hallmarks include deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. Lastly, stem cell exhaustion and altered intercellular communication, known as integrative hallmarks, are indicators of impaired processes at the molecular and cellular levels, and both indicate a loss of reserve capacity or resilience, ultimately producing the aging phenotypes described by Ferrucci et al. (2010) (Fig. 1). The integration of all these hierarchical levels has been defined as metrics of aging (Ferrucci et al., 2018). Therefore, the geriatric syndromes would be considered ‘phenotypic aging’, and the hallmarks of aging should be viewed as ‘biological aging’. Ultimately a desequilibrum in both levels will lead to changes in cognition and physical performance, known as ‘functional aging’, ending in frailty and a loss of resilience.
Fig. 1. Hallmarks of aging and the four domains of aging phenotypes.
Integrative view of the hallmarks of aging described by Lopez-Otin et al. (2013) and the domains of the aging phenotypes described by Ferrucci et al. (2010). Different factors (genes, environment, exercise and nutrition) contribute to the rate of biological aging. The loss of reserve capacity or resilience, at a molecular and cellular level, ultimately leads to the development of the aging phenotypes.
In the last two decades, major scientific advances in our understanding of aging processes were achieved in model organisms, which led to the discovery of conserved longevity pathways, as well as the development of genetic, nutritional, and pharmacological interventions that target them. It is likely that the same interventions may provide benefits only in select tissues, organisms, or individuals based on age, sex, and ethnicity (Bartke et al., 2019). In model organisms, lifespan extension is often accompanied by a reduction or delay in morbidity (Fontana et al., 2010). Many of the pro-longevity pathways are also implicated in tissue development and metabolic regulation, as restriction in calorie intake is considered a key modulator in the aging process (de Cabo et al., 2014; Mercken et al., 2012). Drugs that mimic the effects of calorie restriction (CR) have shown life- and healthspan-extending properties through modulation of nutrient-sensing pathways, mitochondrial stress and antioxidant responses, and chromatin silencing (de Cabo et al., 2014; Lopez-Otin et al., 2016).
One of the most active areas of research in aging focuses on the identification of novel pathways that regulate the underlying processes of aging in order to develop interventions aimed at delaying the onset and progression of chronic diseases, preservation of functional capacity, and postponing death. We surmise that increases in mean lifespan with compression of morbidity is an ambitious, yet achievable goal within our reach (Fries et al., 2011; Ebeling et al., 2018), although translation of the advances made from model organisms to human clinical trials still remains a major challenge (Campisi et al., 2019). Nevertheless, there are multiple questions that persist on how to reverse or delay the dysregulation of biological systems that are implicated in age-associated phenotypic changes that lead to frailty and death. In this review, we considered pharmacological interventions that lead to lifespan extension and/or increase or preservation of function in mammals and human by targeting the hallmarks of aging.
2. Interventions that delay aging
Several small molecules and dietary manipulations based on CR have been developed during the last two decades that target processes of aging. A number of compounds have been found to delay the onset of age-related diseases and increase healthspan and lifespan from yeast to mammals, including nonhuman primates (Fontana et al., 2010; Ravussin et al., 2015; Mattison et al., 2017). These interventions target major signaling pathways whose dysregulation contributes to the emergence of aging phenotypes and disease. These compounds are generally considered CR mimetics that extend lifespan through an improvement of metabolic function, especially via mitochondrial metabolic reprogramming, and include drugs that target i) various growth factor signaling pathways; ii) insulin signaling pathway implicated in carbohydrate and fat metabolism; iii) NAD+-dependent sirtuins; iv) amino acid pathway; v) autophagy; vi) senescence; and vii) stem cells and rejuvenation factors. There are excellent recent reviews that have extensively covered the benefits of these CR-mimetic compounds and interventions (Fontana et al., 2010; Longo et al., 2015; Rizza et al., 2014; Fontana et al., 2012; Fontana and Partridge, 2015; de Cabo et al., 2014; Martin-Montalvo and de Cabo, 2013; Baur et al., 2012; Novelle et al., 2015; Pan and Finkel, 2017; Custodero et al., 2018; Gurau et al., 2018). Here, we present a brief overview of the beneficial effects that these drugs and interventions confer on the different hallmarks of aging.



2.1. Drugs targeting growth factor pathways
2.1.1. mTOR inhibitors, rapamycin, rapalogs and other
Rapamycin is an antifungal antibiotic that was first isolated from an Easter Island soil sample by Chang et al. (1991). Rapamycin has been approved by FDA for its immunosuppressive and anti-rejection properties (Camardo, 2003). Novel mTOR inhibitors, known as rapalogues, have the same molecular scaffold as rapamycin, but with different physiochemical properties (Lamming and Sabatini, 2013). The anti-cancer properties of rapamycin are associated with inhibition of the mammalian target of rapamycin (mTOR) through interaction with immunophilin FKBP12, which binds next to the kinase region of TOR, a serine/threonine kinase that is regulated by nutrients, growth factors, and the cellular energy status. TOR signals through two multiprotein complexes, termed mTORC1 and mTORC2, with distinct biological outcomes. Acute and chronic exposure to rapamycin has been shown to inhibit mTORC1 whereas inhibition of mTORC2 requires long-term treatment with the drug (for review, see Li et al., 2014). The pro-longevity effects of rapamycin are conveyed through mTORC1 whereas mTORC2 inactivation is believed to be responsible of the insulin resistance phenotype associated with rapamycin treatment (Saxton and Sabatini, 2017).
mTOR is considered a “metabolic master regulator” through its ability to regulate metabolism across metabolically active tissues, such as skeletal muscle, adipose tissue, liver and brain (Sengupta et al., 2010; Tsai et al., 2015; Lamming and Sabatini, 2013; Garelick and Kennedy, 2011). Inhibition of mTORC signaling can also have protective effects during obesity and type 2 diabetes (Reifsnyder et al., 2018). The healthspan and lifespan extension properties of rapalogs stem from the lowering in mTOR signaling pathway activation triggered by insulin/IGF-1 axis, amino acids and glucose levels, all of which acting in concert to influence the cellular energy status (for review see Kennedy and Lamming, 2016). Pharmacological inhibition of TOR with rapamycin or other mTOR inhibitors promotes lifespan extension in yeast, worm, flies, and mice (Vellai et al., 2003; Cao et al., 2010; Robida-Stubbs et al., 2012), notably by impacting downstream mTORC1-regulated processes that include autophagy, lipid synthesis, mitochondrial metabolism, ribosomal biogenesis, and modulation of the senescence-associated secretory phenotype among others (Pan and Finkel, 2017). The pro-longevity effects of rapamycin are seen preferentially in females than males (Miller et al., 2014). Recently, it has been suggested that the effects of mTORC1 inhibitors, such as the rapalog RAD001, could be mediated by regulation of c-Myc protein, with subsequent reduction in nephropathy lesions found in aged rats (Shavlakadze et al., 2018).
2.2. Drugs targeting insulin signaling pathways, carbohydrates and fat metabolism
2.2.1. Metformin
Metformin (N,N-dimethylbiguanide) belongs to the biguanide class of anti-diabetic drugs and is well tolerated compared to other drugs. Metformin is most commonly used as a first-line medication for type 2 diabetes by lowering hepatic glucose production and insulin resistance. The underlying mechanisms by which metformin inhibits hepatic gluconeogenesis remains unknown, although recent studies have shown that metformin could suppress gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase (Madiraju et al., 2014) and by activation of a duodenal pathway dependent on AMP-activated protein kinase (AMPK) (Duca et al., 2015). One of the major clinical advantages of metformin is that it does not induce hypoglycemia or weight gain while correcting hyperglycemia and conferring CR-like benefits such as improvement in insulin sensitivity and AMPK activity and better antioxidant protection. The ability of metformin at improving healthspan and lifespan of drosophila, C. elegans and mice raises the possibility of metformin-based interventions to promote healthy aging in humans (Slack et al., 2012; Cabreiro et al., 2013; Martin-Montalvo et al., 2013; Novelle et al., 2016; Alfaras et al., 2017). Metformin has been reported to abrogate DICER1-mediated cellular senescence by altering microRNA expression (Noren Hooten et al., 2016) and producing epigenetic modifications that regulate the expression levels of several microRNAs to confer protection against diabetes and cancer (Bridgeman et al., 2018). A 6-week treatment with metformin regulates several cellular processes (e.g., DNA repair) and metabolic pathways that include pyruvate metabolism, PPAR and SREBP signaling, and mitochondrial fatty oxidation in skeletal muscle and subcutaneous adipose tissue of older adults (Kulkarni et al., 2018). While neonatal exposure to metformin appears to slow aging down and prolongs lifespan in male mice (Anisimov et al., 2015), administration of the biguanide every other week when initiated in late-life leads to an overall improvement on health without an extension in lifespan as compared to control mice (Alfaras et al., 2017). Long-term metformin treatment has been found to lower the expression of the antioxidant regulator Nrf2 (Nfe2l2) and that of neurotrophic factors in the brain of old mice (Allard et al., 2016).
Based on experimental evidences from cellular and animal studies, a recent clinical trial known as TAME (Targeting Aging with Metformin) will assess whether metformin can delay the onset and/or progression of age-related diseases beyond its effects on glucose metabolism. TAME plans to enroll 3000 subjects, ages 65–79, in 14 different centers across the U.S. (Barzilai et al., 2016). Intriguingly, recent studies have found that the combination of metformin with exercise opposes the exercise-induced benefits in insulin sensitivity, cardiorespiratory fitness, and mitochondrial adaptations to aerobic exercise in older adults (Malin et al., 2012; Konopka et al., 2019).
2.2.2. 17α -Estradiol
While the feminizing hormone 17β-estradiol (17β-E2) is the most biologically active and abundant estrogen in circulation, 17α-estradiol (17α-E2) is considered a non-feminizing hormone with reduced affinity for the estrogen receptor. Previous studies have shown that 17α-E2 can confer protection against oxidative stress and age-related degenerative brain disorders, such as Parkinson’s and Alzheimer’s diseases, and age related inflammation (Dykens et al., 2005; Santos et al., 2017). Exposure to 17α-E2 reduces body weight and extends lifespan in male mice while mitigating metabolic and age-related chronic inflammation (Stout et al., 2017). The fact that 17α-E2 extends longevity of male but not female mice suggests a sexual dimorphism in its effect on lifespan (Strong et al., 2016; Harrison et al., 2014) that is reminiscent of acarbose (Harrison et al., 2014). Gonadectomised male and female mice have shown the contribution of sex hormones as main regulators of sexual dimorphism toward the lifespan extension properties of 17α-E2 and acarbose (Garratt et al., 2017). A recent study has shown that 17α-E2 treatment in male mice does not increase the contribution of protein synthesis to proteostatic processes in metabolically active tissues, contrary to what has been shown in energy-restricted models or long-lived organisms (Miller et al., 2019). Further studies are required to elucidate the molecular mechanism of 17α-E2 action.
2.2.3. Acarbose
Acarbose is an alpha-glucosidase inhibitor that inhibits intestinal digestion of carbohydrates. Used for more than 20 years to treat hyperglycemia and type 2 diabetes, acarbose is considered a CR mimetic capable of lowering postprandial blood glucose levels as well as total cholesterol, triglycerides and low-density lipoprotein cholesterol levels while enhancing insulin sensitivity in mice (Yamamoto and Otsuki, 2006; Gentilcore et al., 2011; Santilli et al., 2010). As indicated above, acarbose extends median and maximal lifespan, and improves healthspan preferentially in male mice through an increase in fibroblast growth factor-21 (FGF21) and a decrease in insulin-like growth factor 1 (IGF1) (Harrison et al., 2014). The exact mechanisms of acarbose action toward healthspan remain unclear.
2.2.4. Fibroblast growth factor-21
FGF21 is a member of the FGF superfamily involved in the endogenous regulation of glucose, lipid metabolism, and inflammation (Nies et al., 2016). This protein hormone attenuates growth hormone (GH)/IGF1 signaling and has been proposed as a therapeutic target for aging and age-related incidence of diabetes and obesity (Mendelsohn and Larrick, 2012). FGF21 delays endothelial replicative senescence by protecting cells from DNA damage and premature senescence through SIRT1 (Yan et al., 2017). FGF21, via its co-receptor β-Klotho, crosses the blood brain barrier to reduce the levels of insulin, inhibit growth, and increase corticosterone levels, thus potentially leading to the development of new treatments for obesity and metabolic disorders (Hsuchou et al., 2007; Bookout et al., 2013). Transgenic overexpression of FGF21 extends lifespan in mice without reducing food intake or affecting either NAD+ metabolism or the regulation of mTOR signaling by AMPK (Zhang et al., 2012). Although the precise mechanism of action is poorly understood, FGF21 could affect longevity and healthspan through alterations of key metabolic pathways reminiscent of CR mimetics, e.g., improvement in cellular longevity through activation of autophagy, stress resistance, and survival signals while attenuating cellular growth and protein synthesis (Xie and Leung, 2017).
2.3. Drugs targeting the NAD+-dependent sirtuins
2.3.1. Resveratrol
Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenol abundant in mulberries, peanuts, and the skin of red grapes. Supplementation of the normal diet with resveratrol extends lifespan and healthspan across a variety of species from yeast, C. elegans and small mammals to non-human primates (McCormack et al., 2015; Fiori et al., 2013; Jimenez-Gomez et al., 2013; Mattison et al., 2014; Bernier et al., 2016). Resveratrol elicits beneficial health effects by suppressing inflammation, oxidative damage, tumorigenesis, and immunomodulatory activities, thereby leading to improvement of mitochondrial function and protection against obesity, cancer, and cardiovascular dysfunction (Xia et al., 2008; Shin et al., 2009; Cho et al., 2017; Wang et al., 2018a, b; Novelle et al., 2015). Recent evidence suggests an attenuation of the inflammatory response in immune and endothelial cells by resveratrol (Schwager et al., 2017), which occurs likely through activation of SIRT1 and AMPK (Ohtsu et al., 2017). Moreover, resveratrol confers neuroprotection in human neural stem cells via AMPK activation and subsequent reduction in β-amyloid-induced inflammation and oxidative stress (Chiang et al., 2018). The inhibition of high-fat diet-induced NFκB signaling pathway also explains the anti-inflammatory effect of resveratrol (Pearson et al., 2008).
A cellular model of Alzheimer's disease has helped to demonstrate that resveratrol attenuates oxidative damage through mitophagy activation (Wang et al., 2018a). Resveratrol alleviates the development of alcoholic liver injury and progression to fatty liver disease by down-regulating hepatic HIF-1α expression and mitochondrial ROS production (Ma et al., 2017). Low dose of resveratrol improves mitochondrial respiratory function and enhances cellular reprogramming in patient-derived fibroblasts with mitochondrial DNA mutations (Mizuguchi et al., 2017). More recently, it has been shown that treatment of diabetic mice with resveratrol increases mitochondrial biogenesis and inhibits the activation of mitophagy in skeletal muscle, thus ameliorating diabetes-induced skeletal muscle atrophy (Wang et al., 2018b).
Although resveratrol exhibits some CR-like benefits on healthspan, its limited absorption and bioavailability are impediment to its effective use. Several studies have shown over the past years that the concentration of resveratrol and its metabolites in urine and plasma are very heterogeneous among individuals on resveratrol supplementation, suggesting that some genetic factors, especially genes from the CYP450 enzymes, could be affecting the response to resveratrol treatment (Walle et al., 2004; Ortuño et al., 2010; Chang et al., 2001). In older community-dwelling adults, total urinary resveratrol metabolite concentration derived from normal diet was not associated with inflammatory markers, cardiovascular disease, and/or cancer or predictive of all-cause mortality (Semba et al., 2014). McDermott et al. (2017) found that resveratrol supplementation didn’t improve walking performance in older people with peripheral arterial disease. Similarly, Pollack et al. (2017) showed that resveratrol treatment improved vascular function and mitochondrial number but not glucose metabolism or insulin sensitivity. Conflicting results have been shown about the effects of resveratrol in lifespan extension in mice, with some authors reporting no pro-longevity effect (Pearson et al., 2008; Miller et al., 2011; da Luz et al., 2012) while others found positive benefits of resveratrol when mice were fed high-fat diet or under intermittent fasting feeding protocols, but not on standard diet (Novelle et al., 2015; Strong et al., 2013; Pearson et al., 2008; Pallauf et al., 2016).
The molecular mechanisms of action of resveratrol remain elusive; however, AMPK and the NAD+-dependent deacetylase SIRT1 have been proposed to mediate the anti-aging response and disease protection of resveratrol, reminiscent of CR signaling (Baur et al., 2006; Park et al., 2012; Kulkarni and Canto, 2015). Understanding how resveratrol exerts its beneficial effects in healthspan will help to develop new drugs to treat age-associated metabolic disorders.
2.3.2. Sirtuin-activating compounds (STACs): SRT1720, SRT2104 and SRT3025
SIRT1 and the other six members (SIRT2-7) of the highly conserved class III histone deacetylase family are positively associated with lifespan (Hubbard and Sinclair, 2014). These seven mammalian sirtuins have different subcellular locations and functional properties, and their activation have been linked to delayed aging, improved metabolism, and oxidative stress resistance in different animal models (Sinclair and Guarente, 2014). Compared to resveratrol, sirtuin-activating compounds (STACs) show better potency, solubility, and target selectivity by binding to the N-terminal domain in SIRT1 (Sinclair and Guarante, 2014), which results in the activation of pro-longevity pathways that target oxidative stress, inflammation and mitochondrial function (Imai and Guarente, 2016; Nogueiras et al., 2012). Pharmacological activation of SIRT1 with SRT1720 and SRT2104 promotes healthspan and lifespan extension via reduction of inflammatory pathways (Minor et al., 2011; Mitchell et al., 2014; Mercken et al., 2014; Bonkowski and Sinclair, 2016). SRT1720 inhibits circulating TNF-α and IL-6 levels in a mouse model of estrogen-induced cholestatic liver injury (Yu et al., 2016), and postnatal administration of SRT1720 attenuates obesity and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy (Nguyen et al., 2018). SRT1720 treatment lowers multi-organ injury and inflammation in mice via reduction of sepsis-induced inflammasome activation, thus attenuating renal fibrosis through apoptosis and reduction of oxidative stress (Ren et al., 2017). Furthermore, SRT1720 confers protection against endothelial senescence, resulting in the maintenance of cellular function via Akt/eNOS/VEGF axis (Li et al., 2016). Aged human mesenchymal stem cells can be rejuvenated by SRT1720-mediated SIRT1 activation of apoptosis (Liu et al., 2017). Another characterized STAC, SRT2104, has been found to increase mitochondrial oxidative phosphorylation and to decrease serum cholesterol and triglycerides in older adults (Libri et al., 2012). Treatment of diet-induced obese mice with SRT2104 promotes body weight loss, improves insulin sensitivity, and increases exercise capacity (Qi et al., 2010); however, these benefits have not been reported in humans (Baksi et al., 2014). Short-term use of SRT2104 extends survival of male mice and preserves bone and muscle mass in an experimental model of atrophy (Mercken et al., 2014). Clinical trials involving patients with type 2 diabetes have shown SRT2104 to be associated with weight loss and improved glycemic control without effects on lipids or platelet function (Noh et al., 2017). Administration of SRT2104 in participants with diabetes lessened aortic endothelial dysfunction via inhibition of p53 (Wu et al., 2018). SRT2104 treatment confers neuroprotection and lifespan extension in a mouse model of Huntington's disease by virtue of its ability to cross the blood-brain barrier and attenuate brain atrophy while improving motor function (Jiang et al., 2014). A third characterized and selective SIRT1 activator, SRT3025, has been linked to hematopoietic stem cell expansion (Zhang et al., 2015) and inhibition of osteoclast generation and function in bone marrow-derived macrophages, a finding suggestive of a role for STACs in combatting osteoporosis (Gurt et al., 2015).
Despite extensive evidence for the delay of phenotypic aging and age-related diseases, more research is needed to elucidate the positive benefits of STACs to treat inflammation, metabolic disorders, and neurodegenerative diseases. See the recent review on the role of STACS in aging by Bonkowski and Sinclair (2016).
2.3.3. Drugs targeting NAD biosynthesis
Interventions such as CR and exercise increase the levels of nicotinamide adenine dinucleotide (NAD+), thus resulting in improved mitochondrial function (Canto et al., 2010; Liu et al., 2008). The decline in cellular NAD+ concentrations with aging is associated with neurodegeneration and other pathologies that adversely impact healthspan and lifespan; conversely, modulation of NAD+ levels appears to be a key factor for successful aging (Gomes et al., 2013; Gong et al., 2013; Mouchiroud et al., 2013). NAD+ fuels reduction-oxidation reactions and regulates a variety of biological processes, including metabolism and stress response, and mediates also some of the beneficial prolongevity effects of intermittent fasting and CR, possibly through sirtuin activation (Bonkowski and Sinclair, 2016; Rajman et al., 2018; Imai and Guarente, 2016). The circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. eNAMPT is carried in extracellular vesicles (EVs) and enhances NAD+ biosynthesis to increase lifespan in mice (Yoshida et al., 2019). Diet supplementation with nicotinamide, a NAD+ precursor, has been recently reported to protect liver function, glucose metabolism and overall health of old mice on high-fat diet without beneficial effect on lifespan (Mitchell et al., 2018). Earlier studies with two other NAD+ precursors, namely nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), have been found to extend healthspan and lifespan in Drosophila and yeast (Anderson et al., 2003; Balan et al., 2008). Administration of NMN ameliorates the impact of maternal obesity on offspring liver health in mice (Uddin et al., 2017) as well as cognitive function via neurovascular coupling in old mice (Tarantini et al., 2019). Improvement in endothelial blood flow and physical endurance in old mice on NMN is the result of SIRT1-dependent increase in both capillary density and hydrogen sulfide production (Das et al., 2018). Renal SIRT1 activity and NAD+ content are restored upon NMN treatment of young and 20-month-old mice (Guan et al., 2017), and NMN can synergize with exercise to delay skeletal muscle dysfunction in aging rats via increase in SIRT1 activity (Pajk et al., 2017).
In a mouse model of Alzheimer’s disease, NR treatment reduces DNA damage, neuroinflammation, and apoptosis of hippocampal neurons while promoting an increase in brain SIRT3 activity that leads to an improvement in cognitive function and hippocampal synaptic plasticity (Hou et al., 2018). NR supplementation attenuates the development of heart failure in a mouse model of dilated cardiomyopathy (Diguet et al., 2017), and stimulates hematopoiesis through increased mitochondrial clearance in immunodeficient mice (Vannini et al., 2019).
In humans, a recent clinical trial showed that chronic NR supplementation is well tolerated and stimulates NAD+ metabolism in healthy middle-aged and older adults (Martens et al., 2018).
As a whole, these results indicate that supplementation with NAD+ precursors is a promising intervention strategy to delay aging and reduce age-associated ailments. However, pharmaco-kinetics or pharmacodynamics studies with these compounds are missing and more work is needed to elucidate the exact mechanisms by which these drugs can improve healthspan and lifespan.
2.4. Interventions targeting amino acid pathways
Although the reduction in calorie intake does not always extend lifespan (Mattison et al., 2012; Mitchell et al., 2016), restriction in specific dietary components, such as proteins or amino acids, has been linked to the control of lifespan from yeast to humans (Leto et al., 1976; Grandison et al., 2009; McIsaac et al., 2016). The mechanisms underlying the role of methionine and other amino acids in delaying aging remain unclear, but may involve reductions in serum IGF-1 coupled with lower oxidative stress and autophagy (Mirzaei et al., 2014; Ables and Johnson, 2017; Liu et al., 2015). Animals on methionine- or tryptophan-restricted diets live longer and show significant reduction in age-related diseases partly though detoxification of mitochondrial ROS (Gonzalez-Burgos et al., 1998; Edwards et al., 2015; Obata and Miura, 2015; Gomez et al., 2015). Adipose tissue and liver are particularly responsive to methionine restriction (Ghosh et al., 2014; Wanders et al., 2015, 2016; Ables and Johnson, 2017), although other organs such as brain, heart and kidneys also benefit from this intervention (Cooke et al., 2018; Grant et al., 2016; Vogel et al., 2017; Marti-Carvajal et al., 2017). One recent study shows clear modulation of gut hormones, weight loss, energy balance, and gut microbiota in rats subjected to tryptophan restriction (Zapata et al., 2018). Moreover, the circadian clock (Nascimento et al., 2013) as well as brain plasticity and normal development (Serfaty et al., 2008) are influenced by tryptophan supplementation in mice. It is imperative that nutritional intervention studies with amino acid restriction be performed in humans.
2.5. Drugs targeting autophagy
Autophagy is a recycling mechanism that helps maintain cellular homeostasis and energetic balance (Sridhar et al., 2012; Singh and Cuervo, 2011). Several types of autophagy have been described and include macroautophagy, microautophagy, and chaperone-mediated autophagy (Singh and Cuervo, 2011), whose effects on health and disease have garnered attention over the years. With aging, there is progressive loss of proteostasis characterized by dysregulation in autophagy, ubiquitin-mediated degradation, and protein synthesis (Lopez-Otin et al., 2013). Aging and age-related diseases have been associated with changes in polyamine levels (Minois, 2014; Gupta et al., 2013) and their role in autophagy (Basisty et al., 2018). The impact of polyamines on cell growth, survival and proliferation has been ascribed to the inhibition of DNA methylation and tumorigenesis in mice (Soda et al., 2013).
Spermidine is a naturally occurring polyamine that elicits beneficial anti-aging effects through regulation of autophagy and other mechanisms, including antioxidant protection (Madeo et al., 2018a). Moreover, spermidine mediates lifespan extension in yeast via inhibition of histone acetylases and activation of autophagy genes, such as atg7, atg11 or atg15 (Morselli et al., 2009). Spermidine extends lifespan in several animal species via MAPK pathway (Minois, 2014) and is effective in improving neurodegeneration and conferring cardioprotection through autophagy (LaRocca et al., 2013; Buttner et al., 2014; Sigrist et al., 2014; Eisenberg et al., 2016). Spermidine supplementation is safe in humans and has positive effects on cognitive function of older adults (Schwarz et al., 2018) and on blood pressure (Eisenberg et al., 2016). The recent review by Madeo et al. (2018b) provides in-depth information about the role of spermidine in aging and disease.
2.6. Drugs targeting senescence pathways
Age-related accumulation of senescent cells in various tissues and organs is associated with several deficiencies that include (1) the decline in the number of stem cells that rely on proliferation for their proper function, (2) weakening of the immune system, (3) inadequate repair capacity, and (4) reduced global and site-specific DNA methylation in aging tissues (Sidler et al., 2014; LeBrasseur et al., 2015). The clearance of p16Ink4a-positive senescent cells delays age-related disorders (Baker et al., 2011) and evidence suggests that genes implicated in cellular senescence are also linked to longevity and age-related diseases (Tacutu et al., 2011). Senolytics refer to small molecules that can induce apoptosis in senescent cells and capable of promoting lifespan extension while delaying the onset of age-related diseases (Kirkland et al., 2017). Originally developed as common anticancer drugs, navitoclax, quercetin, and dasatinib have senolytic properties (Ranganathan et al., 2015; Tolcher et al., 2015) that target BCL-2 and related anti-apoptotic pathways (Zhu et al., 2017). Alvespimycin is a potent HSP90 inhibitor with senolytic properties (Fuhrmann-Stroissnigg et al., 2017). Other senolytics include fisetin, a naturally-occurring flavone with low toxicity, and the BCL-XL inhibitors, A1331852 and A1155463, that have similar reactivity as navitoclax but with less hematological toxicity (Zhu et al., 2017). Clearance of senescent cells with chronic senolytic treatment improves age-related vascular conditions and reduces mortality from cardiovascular disease (Roos et al., 2016). For example, the treatment of aged mice with navitoclax eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice (Walaszczyk et al., 2019). The combination of dasatinib plus quercitin has been recently shown to improve physical function and increase lifespan in old mice (Xu et al., 2018) and ameliorates Aβ plaque-associated inflammation and cognitive deficits in Alzheimer’s disease mice (Zhang et al., 2019).
The ability of senolytic drugs to reduce the number of senescent cells and combat inflammatory diseases, such as obesity and other metabolic disorders, constitutes a major therapeutic approach aimed at ensuring healthy aging (Palmer et al., 2019). In fact, an open-label pilot clinical study has recently demonstrated that quercitin could alleviate idiopathic pulmonary fibrosis (Justice et al., 2019). The recent review of Kirkland et al. (2017) provides additional insight into this important class of compounds.
2.7. Rejuvenation factors (GDF11, GDF8)
Studies of heterochronic parabiosis have provided evidence of rejuvenation factors present in the blood of young mice (e.g., cells and proteins) that provide benefits in aged animals (Conboy et al., 2005). Systemic administration of young blood counteracts age-related decline in cognitive function and synaptic plasticity in mice (Villeda et al., 2014). Growth/differentiation factor 11 (GDF11) and GDF8, both members of the transforming growth factor (TGF)-β superfamily, have been identified as rejuvenation factors (Loffredo et al., 2013; Sinha et al., 2014). Circulating concentrations of GDF11 correlate with lifespan in mice (Zhou et al., 2016), and several studies have shown that the decline in circulating GDF11 in old mice can be restored, via parabaiosis or injection of the recombinant form, with concomitant reduction in age-related cardiac hypertrophy (Loffredo et al., 2013; Sinha et al., 2014). Daily injections of GDF11 also improves cerebral vasculature and increases the number of brain stem cells (Katsimpardi et al., 2014). However, other studies have reported the lack of pro-longevity effects of GDF11 in a mouse model of premature aging (Freitas-Rodriguez et al., 2016), and GDF11 treatment does not appear to rejuvenate skeletal muscle stem cells in old mice (Hinken et al., 2016). In humans, there is no evidence to suggest that GDF11 levels decline with age, although low GDF11 has been associated with frailty and morbidity in older adults with cardiovascular disease (Schafer et al., 2016).
The contribution of these rejuvenation factors in aging research has been controversial (Egerman et al., 2015; Smith et al., 2015), and it is based mostly on the lack of accuracy in quantifying GDF11 and GDF8. More work is needed to assess whether these and other rejuvenation factors can reverse aging phenotypes in both mice and its potential translation into humans.

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