Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop

Abstract

The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, or life span spent free of significant disease and disability. Studies are underway to examine several possible pharmacological interventions for this purpose. As part of a National Institute on Aging workshop on the development of function-promoting therapies, scientific content experts provided literature reviews and state-of-the-field assessments for the studies of senolytics, nicotinamide adenine dinucleotide (NAD⁺) boosters, and metformin. Cellular senescence increases with age, and preclinical studies demonstrate that the use of senolytic drugs improves healthspan in rodents. Human studies using senolytics are in progress. NAD⁺ and its phosphorylated form, NADP⁺, play vital roles in metabolism and cellular signaling. Increasing NAD⁺ by supplementation with precursors including nicotinamide riboside and nicotinamide mononucleotide appears to extend healthspan in model organisms, but human studies are limited and results are mixed. Metformin is a biguanide widely used for glucose lowering, which is believed to have pleiotropic effects targeting several hallmarks of aging. Preclinical studies suggest it improves life span and healthspan, and observational studies suggest benefits for the prevention of several age-related diseases. Clinical trials are underway to examine metformin for healthspan and frailty prevention. Preclinical and emerging clinical studies suggest there is potential to improve healthspan through the use of pharmacologic agents reviewed. However, much further research is needed to demonstrate benefits and general safety for wider use, the appropriate target populations, and longer-term outcomes.

Major discoveries in aging research have led to a deeper understanding of the basic mechanisms of aging, and have provided evidence that biological aging can be modified (1). Age is a major risk factor for most chronic diseases, such as cardiovascular diseases, type 2 diabetes, malignancies, and dementia, which contribute to functional decline and loss of independence. As the older adult population grows rapidly (expected to increase from 6.9% to 12% of the population worldwide and from 12.6% to 20.3% in North America by the year 2030) (2), the personal and socioeconomic burdens will be considerable. Over half of older adults have impairments in function, over a quarter have a disability in basic or instrumental activities of daily living, and approximately 14% of those over 70 years of age have dementia (3,4).

The geroscience hypothesis posits that it is feasible to prevent, delay, or ameliorate several age-related diseases simultaneously by targeting the key molecular pathways of aging that also underlie most common age-related diseases. This period of life spent free of significant disease and disability is also referred to as healthspan (1). A major focus of the National Institute on Aging (NIA) and its funded investigators is to examine the effect of interventions on key molecular pathways, or “hallmarks” of aging, and determine whether these interventions lead to improvements in healthspan (5). The current treatment strategies for chronic age-related conditions are focused on the prevention and treatment of single diseases. As individuals grow older and develop many age-related diseases, this single-disease approach that results in polypharmacy becomes expensive, burdensome, and often harmful to older adults (6). Over time, this approach inevitably leads to polypharmacy, with 90% of older adults taking 5 or more medications. Polypharmacy increases the risk of adverse drug events, drug interactions, drug–disease interactions, poor regimen adherence, and an onslaught of geriatric syndromes, such as falls, cognitive decline, delirium, and frailty (7). The geroscience hypothesis is, therefore, a promising paradigm to improve the aging experience by targeting aging itself (8).

This report summarizes oral presentations presented in the NIA-funded workshop, “Development of Function Promoting Therapies: Public Health Need, Molecular Targets, and Drug Development,” in the session titled, “Geroscience Approach: Drugs Targeting Mechanisms of Aging to Prevent and Treat Age-related Diseases.” Although several potential interventions are being investigated, the workshop presentations focused on senolytics, nicotinamide adenine dinucleotide (NAD⁺) boosters, and metformin.

Senolytics

One fundamental aging mechanism is cellular senescence. Multiple studies using animal models, along with some human studies, have established that senescent cells accumulate with age. In mice, clearance of even a subset of these cells has health benefits (for a review, see (9)). Two key triggers of senescence are the cyclin-dependent kinase inhibitors, CDKN2A (p16^Ink4a) and CDKN1A (p21^Cip1). Activation of these pathways leads to a number of downstream events characteristic of senescent cells, including growth arrest, resistance to apoptosis, and the senescence-associated secretory phenotype (SASP), which consists of inflammatory cytokines, chemokines, and metalloproteinases (9). At least 2 distinct approaches have been used to target senescent cells: senolytics, which are directed at the anti-apoptotic pathways that senescent cells rely on for their survival (eg, BCL-2 family inhibitors), and senomorphics, which do not kill senescent cells but inhibit the SASP (eg, JAK 1/2 inhibitors) (9).

In preclinical “proof-of-concept” studies in mice, 3 approaches have been used to evaluate whether targeting senescent cells can prevent age-related morbidities and improve life span. The genetic approach is exemplified by the INK-ATTAC (INK-linked apoptosis through targeted activation of caspase) mouse model, in which either vehicle or a synthetic drug (AP20187, an inducer of dimerizeration), was administered to transgenic mice expressing a “suicide” transgene. Treatment with AP20187 resulted in the inducible elimination of p16^Ink4a-expressing senescent cells without affecting nonsenescent cells (10). Clearance of senescent cells using this genetic approach delayed tumorigenesis, attenuated age-related deterioration of several organs, including kidney, heart, fat, and bone (10,11), and extended life span (10).

The pharmacologic senolytic approach targets senescence-associated anti-apoptotic pathways (SCAPs), which senescent cells rely on for their survival. For example, dasatinib (an FDA-approved tyrosine kinase inhibitor) plus the flavonol quercetin had favorable senolytic effects in mice without untoward side effects, in part because senolytic effects could be achieved by intermittent drug administration (eg, every 2 weeks or monthly) (12). Additional senolytics continue to be described, such as navitoclax (a BCL-2 family inhibitor) and others (for a recent review, see (13)).

The senomorphic approach uses compounds that inhibit the SASP. JAK1/2 inhibitors, rapamycin and related mTORC1 inhibitors, glucocorticoids, and metformin have shown senomorphic activities (9). However, senomorphic drugs likely need to be given continuously and hence have a potentially greater risk of side effects.

Multiple studies demonstrate that these pharmacologic approaches have beneficial effects on age-related changes across tissues in mice, consistent with the predictions of the geroscience hypothesis (8). Some of these compounds have now moved into early-phase clinical trials (for a summary, see (13)). Specifically, treatment with the senolytic combination of dasatinib and quercetin has been demonstrated to clear senescent cells in patients with diabetic kidney disease (14) and result in improvement in measures of physical function in patients with idiopathic pulmonary fibrosis (15). As these studies are initiated, a number of important questions need to be addressed, which we summarize briefly subsequently.

In addition to gathering data on the efficacy of these compounds in humans, safety remains an important concern, even though many of the potential senotherapeutic drugs are repurposed compounds with known safety profiles. For example, some compounds (ie, dasatinib) are primarily used in patients with underlying malignancy, so their use in aging individuals without cancer requires a higher safety threshold. In addition, concerns regarding safety also have to do with the safety of clearing senescent cells. For example, it has been hypothesized that senescence likely evolved as an anti-cancer mechanism, whereby cells that had accumulated oncogenic insults were redirected toward a senescent, growth-arrested phenotype rather than uncontrolled proliferation and cancer (9). Mitigating this concern, however, is the efficacy of the senolytic drugs in mice when given intermittently. In particular, because, at least with aging, senescent cells take weeks (or longer) to accumulate, intermittent dosing (eg, 1–2 times a month) may be adequate to have therapeutic benefits and minimize risks (16). However, additional studies, including pharmacokinetic/pharmacodymanic studies of senolytic compounds, are needed to further evaluate this possibility. Moreover, because senescent cells themselves may promote cancer growth through the pro-inflammatory SASP (9), their elimination may be beneficial. Thus, although the issue of tumor formation must be monitored closely in clinical studies, these considerations suggest that carcinogenesis is unlikely to emerge as a significant concern.

Another concern is that at least in the skin, clearing transient senescent cells during injury delays wound repair (17). However, clearing these cells after bone fracture accelerates fracture healing in mice (18).

Although approaches targeting senescent cells have shown great promise in preclinical studies, much work remains for their ultimate translation as viable therapeutics for humans. There clearly is a need for continued development of new senolytic/senomorphic compounds, perhaps using high-throughput screening technology and in vitro senescence assays. In addition, selection criteria for clinical trials need to be defined. For example, would senolytic or senomorphic compounds work in all aging individuals, or just in those with a high senescent cell burden? As such, there is a need to develop biomarkers to identify individuals most likely to benefit from these therapies and to monitor their response to treatment.

Nicotinamide Adenine Dinucleotide Boosters

Nicotinamide adenine dinucleotide (NAD⁺) and its phosphorylated form, NADP⁺, play important roles in almost every metabolic pathway by carrying electrons in the form of a hydride ion. Without NAD⁺ and NADP⁺, cells cannot synthesize key macromolecules, mount an effective antioxidant response, or maintain any sustainable route to ATP generation. These fundamental redox roles conserve the available pools of each dinucleotide, interconverting NAD⁺ with NADH and NADP⁺ with NADPH. However, NAD⁺ is also a substrate for several families of enzymes that release the nicotinamide moiety while using the ADP-ribose moiety to modify proteins, as an acceptor for acyl groups being removed from proteins or to release free or cyclized ADP-ribose. These reactions require a salvage pathway to regenerate NAD⁺ from nicotinamide. A mismatch between synthesis and consumption could result in the depletion of the NAD⁺ pool. This clearly occurs during certain disease processes, and more subtle declines in tissue NAD⁺ pools appear to be a general feature of aging (19). Thus, decreased NAD⁺ concentrations could be targeted as a strategy to restore healthier or more youthful metabolite levels.

In yeast and flies, increased expression of the NAD⁺ biosynthetic enzyme pyrazinamidase/nicotinamidase 1 (PNC1) increases life span (20,21). However, it is not clear that this manipulation changes steady-state NAD⁺ levels in either organism. Instead, depletion of nicotinamide (by conversion to nicotinic acid) or changes in the NAD⁺/NADH redox state may mediate the effects. Increasing NAD⁺ by supplementation with the precursor nicotinamide riboside (NR) modestly extended life span in model organisms, including mice (22). In contrast, supplementing mice with nicotinamide did not affect longevity (23). Furthermore, a larger multicenter study with NR (albeit at a lower dose than before) that used genetically diverse mice showed no effect on murine longevity (24). Inhibition of the NAD⁺ hydrolase CD38 in mice beginning in middle-age increased median life span by about 10% (25), which was attributed to reduced NAD⁺ degradation. In humans, a 15-year follow-up of the participants in the Coronary Drug Project (9 years after the termination of the trial) revealed a small (11%) but significant decrease in mortality among participants who had received a 6-year course of nicotinic acid (niacin) therapy (26). Whether this is attributable to increased NAD⁺ synthesis versus other effects of niacin (most prominently lipid lowering) is not known. NAD⁺-boosting strategies have had more marked effects in mouse models of human diseases, increasing life span more than three-fold in a model of severe ataxia telangiectasia (27), and improving survival in sepsis (28) and hemorrhagic shock (29). Thus, data on overall survival after NAD⁺ supplementation are limited and suggest at most a modest benefit in healthy organisms, but potentially larger effects in certain disease states.

In addition, preclinical data support the ability of NAD⁺ precursors to improve many functional phenotypes associated with aging (22,30,31). The function of muscle, neural, and melanocyte stem cells improved in mice receiving NR (22) and mice receiving nicotinamide mononucleotide (NMN) displayed improvements in energy metabolism, physical activity, insulin sensitivity, and ocular function (32). Old mice receiving NR (33) or with genetically enhanced NAD⁺ concentrations in skeletal muscle (34) showed increased treadmill endurance. NMN protected against age-related vascular dysfunction and maintained neurovascular coupling (30). NAD⁺ boosting has also shown promise in mouse models of neurodegenerative disease (35). In young mice, NR protects against noise-induced hearing loss (36), light-induced vision loss (37), and muscle wasting in mice with cancer (38), although its efficacy against the corresponding age-related conditions remains to be fully elucidated. Such studies will be important given that NAD⁺ concentration in skeletal muscle was recently correlated with functional status in aged humans (39). Overall, despite many potential benefits of NAD⁺ boosting in preclinical models, the results require validation in human trials and much more work is needed to understand the underlying mechanisms.

Clinical data on the effects of NAD⁺ boosting remain sparse and somewhat inconsistent, although many more trials are in progress. Generally, improvements in physical performance or metabolic parameters have been modest or absent, except for a study in patients with mitochondrial myopathy in which niacin increased NAD⁺ and significantly improved physical function (40). Modest improvements in vascular function and blood pressure (41), decreased expression of inflammatory cytokines (42), protection from acute kidney injury (43), and variable improvements in muscle insulin sensitivity (44,45) have been reported. In addition, a small study in patients with Parkinson’s disease revealed a signature in positron emission tomography (PET) scans that could be correlated to NAD⁺ status in the brain and separately to the rate of change in disease burden (46). The reasons for milder benefits, or failure to recapitulate some findings from animal models in humans, may be severalfold. Most obviously, there could be true interspecies differences in the metabolism of, or need for, NAD⁺. However, it should also be kept in mind that rodent studies have generally employed much higher doses when normalized to body weight. For certain drugs, higher dosing for rodents may be justified based on faster metabolism, but it is not clear that this is the case for NAD⁺, as turnover rates appear similar between human and mouse-derived cell lines (47). Another critical point to keep in mind is that clinical trials to date have generally been limited to a few months, making it a high bar to achieve measurable changes in chronic conditions or functional status.

Boosting NAD⁺ as a test of the geroscience hypothesis has many attractive features. NAD⁺ boosters are forms of vitamin B3 and have been well tolerated in short-term studies. Mechanistically, NAD⁺ and related molecules are involved in almost every aspect of metabolism and many disease processes, and could potentially improve many age-related conditions. Moreover, inflammation and DNA damage, which increase with age, stimulate the activity of key NAD⁺-consuming enzymes, providing a plausible explanation for suboptimal NAD⁺ levels with age. Interventions that promote healthy aging—exercise and caloric restriction—boost NAD⁺ levels in rodents, and emerging data in humans indicate a correlation between skeletal muscle NAD⁺ levels and muscle function (39). Ongoing trials will soon reveal whether restoring NAD⁺ can confer meaningful resilience against multiple age-related conditions, in line with the geroscience hypothesis (1,8).

Metformin

Metformin is the most widely used oral antidiabetic drug, generally recommended as first-line treatment for type 2 diabetes and for diabetes prevention, along with lifestyle modification (48). Although metformin’s glucose-lowering properties are well established, it also improves cardiovascular health and reduces microvascular complications of type 2 diabetes, such as retinal and renal complications. However, emerging evidence shows that metformin extends lifespan in C. elegans nematodes and mice, and improves aging-related declines in functional parameters in mice (eg, exercise tolerance, locomotor activity, glucose intolerance, and cataract development) (49). In humans, several observational studies suggest that metformin reduces cancer, cardiovascular disease, dementia, frailty, and all-cause mortality (50–53). Therefore, given that metformin is well tolerated, safe, and widely used, there is high interest in testing its role as a potential agent to reduce age-related diseases and geriatric syndromes (54,55).

In rodents and humans, metformin lowers blood glucose in part by activating AMP-activated protein kinase (AMPK), an energy sensor and key regulator of lipid and glucose metabolism (56). Other mechanisms implicated in metformin’s glucose-lowering effects include inhibition of mitochondrial respiratory chain complex 1 and hepatic fructose-1,6-bisphosphatase-1, changes in the redox state, and alterations in incretin and bile acid secretion, which may result from changes in the gut microbiome (57), inhibition of complex IV activity leading to a decrease in the activity of glycerol-3-phosphate dehydrogenase activity, and a selective inhibition of glycerol-derived hepatic gluconeogenesis (58). The mechanisms involved in metformin’s glucose-lowering effect likely also contribute to its beneficial effects on aging. Metformin may have other mechanisms of action, which are yet to be fully elucidated, and by which it may impart longevity and aging benefits (59).

Metformin, in part by activating AMPK, modulates several pathways related to the pillars of aging, such as peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)α, a master regulator of mitochondrial function; nrf2, a transcription factor that controls antioxidant programs; and the mammalian target of rapamycin pathway (49). Metformin also reduces systemic and tissue inflammation, reduces insulin/IGF-1 signaling, and inhibits nuclear factor-kappa B activation by blocking phosphorylation of IĸB and IKKα/β (60). Metformin treatment reduces endogenous reactive oxygen species (ROS) in an AMPK-dependent manner, reduces DNA double-strand breaks following paraquat exposure, and attenuates ROS levels and DNA damage induced by Ras expression (61). Metformin can also modulate processes related to epigenetic control of gene expression by inhibiting the activity of histone acetyltransferases, histone deacetylases, and DNA methyltransferases and altering microRNA expression (62). Metformin may influence histone acetyltransferase expression through AMPK-independent mechanisms, and inhibit histone methyltransferase expression and histone ubiquitination (62). Metformin-induced AMPK activation upregulates autophagy via phosphorylation of ULK1 and beclin 1, and may also play a central role in hormesis, increasing stress resistance and life expectancy and potentially increasing resilience against age-related diseases (63). Further, metformin prevents senescence and suppresses SASP in some cell lines (64), and induces a transcriptome in animals similar to that seen in caloric restriction experiments (65). Thus, metformin has pleiotropic effects which may contribute, perhaps collectively, to its aging-modulating properties.

To date, there are few clinical trials of metformin to directly examine metformin’s effects on human healthspan. Espinoza et al. are currently conducting a randomized placebo-controlled clinical trial of metformin to prevent frailty in older adults with glucose intolerance, which will also examine the effects of metformin on several hallmarks of aging (55). This trial focuses on older adults with glucose intolerance, because insulin resistance and hyperglycemia reduce muscle strength and quality and impair physical function (66). In addition, insulin sensitizers such as metformin may attenuate these declines and prevent frailty (51,67). Because metformin use typically does not result in hypoglycemia, it could potentially be used safely in individuals with normal glucose tolerance to confer aging benefits, but this is unknown and has not been examined directly in a clinical trial. One completed study examined the effect of metformin or placebo when combined with aerobic exercise training in adults with prediabetes aged 55 years or older (68), which showed that the metformin group had less improvement in VO₂ Max, insulin sensitivity, and mitochondrial function after aerobic exercise training. However, because there was not a metformin-only treatment group that did not include exercise, it is difficult to extrapolate these results to determine the isolated effects of metformin. Nevertheless, these findings suggest that more research is needed to examine its effects on measures of function. However, given its tolerability and safety profile, metformin could be quickly translated to clinical use if ongoing and future clinical trials demonstrate its efficacy in promoting healthspan.

Translational Issues

Presently, there are many clinical trials of these agents that are relevant to aging or age-related diseases. Although it is beyond the scope of this proceedings paper to provide an extensive review of these trials, we provide a list of active or completed clinical trials of senolytics, NR, or metformin, which are currently registered in clinicaltrials.gov (see Table 1). Beyond determining the safety of these agents, substantial work will be needed to determine what effect any of these interventions have on various domains of healthspan, that is, physical function, cognitive function, frailty, disability, patient-reported outcomes, and health-related quality of life. Further, we will need consensus in the field in order to identify the most meaningful and clinically relevant outcomes. We must also identify the appropriate patient populations for these treatments, which will be informed by the evidence base as clinical trials are conducted and completed. It is likely that no single intervention will be broadly indicated, but that agents will be tailored to the individual person using an individualized, patient-centered approach. Future, larger, pragmatic clinical trials will be needed in order to demonstrate efficacy beyond smaller, early-phase clinical trials. Furthermore, any interventions for older adults must not inadvertently exacerbate existing medical comorbidities or geriatric syndromes, such as contributing to polypharmacy. This will require that physicians and others providing medical care to older adults, the vast majority of which are not geriatricians, must be trained and knowledgeable in basic principles of geroscience and the use of such therapies toward the goal of improving healthspan (as opposed to the traditional single-disease approach). Clinical practice guidelines specific to promoting healthspan in older adults may be needed to guide any future broad clinical use.

Table 1.

Active or Completed Clinical Trials of Senolytics, Nicotinamide Riboside, or Metformin, With Relevance to Aging

Agent(s)	Condition, Disease, or Population	Primary Outcome(s)	Stage and Status	Trial Registration Number
Dasatinib, quercetin	Adults aged 40+ y	Epigenetic age test	Phase 2, active, not recruiting	NCT04946383
Dasatinib, quercetin	Adults aged 65+ y with slow gait speed and mild cognitive impairment	Neurovascular coupling, executive function, gait speed	Phase 1/2, recruiting	NCT05422885
Dasatinib, quercetin	Mild cognitive impairment, Alzheimer’s disease	Safety and tolerability	Phase 1/2, enrolling by invitation	NCT04785300
Dasatinib, quercetin	Alzheimer’s disease	Brain penetrance of dasatinib and quercetin	Phase 1/2, active, not recruiting	NCT04063124
Dasatinib, quercetin	Alzheimer’s disease (early onset), mild cognitive impairment	Serious adverse events	Phase 2, recruiting	NCT04685590
Dasatinib, quercetin	Chronic kidney disease	Total senescent cell burden in blood, skin, or adipose	Phase 2, enrolling by invitation	NCT02848131
Dasatinib, quercetin	Idiopathic pulmonary fibrosis	Several, including inflammation and inflammation markers	Phase 1, completed	NCT02874989
Dasatinib, quercetin	Stem cell transplant recipients	Frailty	N/A, recruiting	NCT02652052
Dasatinib, quercetin, lifestyle intervention	Obesity	Insulin sensitivity, glucose tolerance	Early Phase 1, not yet recruiting	NCT05653258
Dasatinib, quercetin, fisetin	Adult 18+ y with history of childhood cancer, frail	Gait speed, senescent cell abundance in blood	Phase 2, recruiting	NCT04733534
Dasatinib, quercetin, fisetin	Women aged 70+ y	Markers of bone turnover in blood	Phase 2, recruiting	NCT04313634
Dasatinib	Adults 18+ y with scleroderma pulmonary interstitial fibrosis	Adverse events and death	Phase 1/2, completed	NCT00764309
Quercetin	Adults 18+ y with coronary artery disease and planned coronary artery revascularization surgery	Inflammation and senescence markers in blood	Phase 2, recruiting	NCT04907253
Fisetin	Frailty	Inflammation markers in blood	Phase 2, recruiting	NCT03675724
Fisetin	Females aged 70+ y	Gait speed	Phase 2, recruiting	NCT03430037
Fisetin	Diabetic and chronic kidney disease	Inflammation markers in blood, stem cell function	Phase 2, enrolling by invitation	NCT03325322
Fisetin	Adults aged 40–80 y with knee osteoarthritis	Treatment-emergent adverse events	Phase 1/2, active, not recruiting	NCT04210986
Fisetin	Adults 18–80 y of age with femoroacetabular impingement	Treatment-emergent adverse events	Phase 1/2, recruiting	NCT05025956
Fisetin	Aged 65+ y, resident of long term care facility, with COVID-19 infection	COVID-19 severity	Phase 2, enrolling by invitation	NCT04537299
Fisetin	Adults 18+ y with COVID-19	Hospitalization or death with COVID-19	Phase 2, enrolling by invitation	NCT04771611
Fisetin	Adults 18+ y with COVID-19	Serious adverse events, oxygenation status	Phase 2, enrolling by invitation	NCT04476953
Fisetin, losartan	Adults aged 40–85 y with knee osteoarthritis	Treatment-emergent adverse events	Phase 1/2, recruiting	NCT04815902
UBX1325 (intravitreal injection)	Adults 50+ y of age with macular degeneration	Safety and tolerability	Phase 1, completed	NCT04537884
UBX1325 (intravitreal injection)	Adults aged 18+ y with diabetic macular edema	Safety and tolerability	Phase 2, active, not recruiting	NCT04857996
NAD3	Adults aged 40–60 y	Body weight, blood pressure, blood lipids	N/A, completed	NCT04276948
Nicotinamide riboside	Adults aged 60–85 y	Neurovascular coupling, neuronal activity	Phase 4, not yet recruiting	NCT05483465
Nicotinamide riboside	Adults aged 70–80 y	Mitochondrial function and NAD+ levels in skeletal muscle	Phase 2, unknown	NCT02950441
Nicotinamide mononucleotide	Adults aged 40–65 y	Blood cellular NAD+/NADH, six minute walking endurance test	N/A, completed	NCT04823260
Nicotinamide riboside, fasting, aerobic exercise	Older adults aged 65+ y	Interleukin-6 levels in plasma	Phase 2, recruiting	NCT05593939
MIB-626	Alzheimer’s disease (including subtypes), dementia	MIB-626 concentrations in cerebrospinal fluid	Phase 1/2, recruiting	NCT05040321
Nicotinamide riboside	Adults aged 50+ y	Systolic blood pressure	Phase 2, recruiting	NCT03821623
Nicotinamide riboside	Yong adults aged 18–35 y and older adults aged 60–75 y	NAD+ levels in blood and peripheral blood mononuclear cells	N/A, completed	NCT03501433
Nicotinamide riboside	Adults aged 18+ y undergoing allogeneic hematopoietic cell transplantation	Tolerability, adverse events	Early Phase 1, recruiting	NCT04332341
Nicotinamide riboside	Parkinson’s disease	Cerebral NAD levels, CSF NAD levels, nicotinamide riboside related pattern by PET imaging	N/A, recruiting	NCT05589766
Nicotinamide riboside	Older adults aged 65–80 y	Maximal oxygen uptake, skeletal muscle function, short physical performance battery, muscle respiration rate, muscle gene and protein expression, bone metabolism	N/A, recruiting	NCT03818802
Niagen	Adults aged 55–79 y	Treatment-emergent adverse events	Phase 1/2, completed	NCT02921659
Nicotinamide riboside	Older adults aged 65–85 y	Maximal oxygen uptake, muscle strength, gait speed	N/A, not yet recruiting	NCT04691986
Niagen	Adults aged 60+ y	Cognitive performance	N/A, completed	NCT04078178
Nicotinamide riboside, exercise	Adults aged 55+ y with hypertension	Systolic blood pressure	Phase 1, recruiting	NCT04112043
Metformin	Older adults aged 65+ y with impaired glucose tolerance	Frailty	Phase 2, active, not recruiting	NCT02570672
Metformin	Adults aged 30–70 y with prediabetes	Autophagy, measured by leukocyte LC3 score	Phase 3, completed	NCT03309007
Metformin	Adults aged 40–75 y	Insulin sensitivity, mitochondrial function	Phase 3, recruiting	NCT04264897
Metformin	Adults aged 60+ y with impaired glucose tolerance	Transcriptome in muscle and adipose	Phase 4, completed	NCT02432287
Metformin	Adults aged 21–80 y with metabolic syndrome	Arterial stiffness, flow mediated dilation	Phase 2, completed	NCT00105066
Metformin	Older adults aged 65+ y with abdominal obesity	Brain ATP production,	Phase 2, active, not recruiting	NCT03733132
Metformin	Adult aged 60+ y with planned elective surgery	Hospital free days	Phase 3, completed	NCT03861767
Metformin	Adults aged 40–75 y with impaired fasting glucose	Longevity gene expression	Phase 4, completed	NCT01765946
Metformin	Adults aged 55–85 y	Cytokine response in blood and peripheral blood mononucleocytes	Phase 1/2, completed	NCT03772964
Metformin	Older adults aged 65+ y	Total lean mass	Phase 1/2, completed	NCT01804049
Metformin	Older adults aged 65+ y with amnestic cognitive impairment	Total recall, Alzheimer’s Disease Assessment Scale–Cognitive Subscale	Phase 2, completed	NCT00620191
Metformin	Adults aged 18+ y with pulmonary hypertension, heart failure	Mean pulmonary artery pressure	Phase 2, recruiting	NCT03629340
Metformin	Adults aged 60+ y with heart failure with preserved ejection fraction	Peak oxygen capacity with exercise	Phase 2, recruiting	NCT05093959
Metformin, lifestyle intervention	Older adults 65–85 y with obesity	Modified physical performance test	Phase 3, recruiting	NCT04221750
Metformin, lifestyle intervention	Adults aged 60–79 y with cognitive impairment and overweight or impaired fasting glucose	Cognition	Phase 2, not yet recruiting	NCT05109169
Metformin, exercise	Older adults 65+ y	Type 2 myofiber cross sectional area	Early Phase 1, completed	NCT02308228
Metformin, bed rest	Adults aged 60+ y	Muscle size, insulin sensitivity	Early Phase 1, recruiting	NCT03107884
Metformin, sirolimus, diclofenac (topical)	Females aged 55+ y	Gene transcripts in skin	Phase 1, completed	NCT03072485
Metformin, influenza vaccine	Older adults 65+ y	Cell-mediated influenza vaccine response	Phase 1, completed	NCT03996538
Metformin, pneumococcal vaccine	Adults aged 63–90 y	Antibody response to pneumococcal vaccine	Phase 1, active, not recruiting	NCT03713801

Notes: COVID-19 = coronavirus disease 2019; NAD⁺ = nicotinamide adenine dinucleotide.

Conclusion

Remarkable advances have occurred in understanding the mechanisms underlying the aging process and the risk factors for poor health status with aging. The fields of aging and geriatrics are entering an exciting new age of discovery in which preclinical studies have unveiled several promising new strategies for the diseases and syndromes of aging.

Funding

S.E. is supported by National Institutes of Health (NIH) grants R01 AG052697, R01 AG069690, R25 AG073119, and P30 AG044271. S.K. is supported by NIH grants P01 AG062416, R01 AG0676415, and R21 AG065868. J.A.B. is supported by NIH grant R01 DK098656. N.M. is supported by NIH grants R01 AG075684, R01 AG06960, U01 AR071130, T32 AG021890, U54 AG075941, P30 AG013319, and P30 AG044271.

This supplement is sponsored by the National Institute on Aging (NIA) at the National Institutes of Health (NIH).

Conflict of Interest

None declared.