Key Researchers & Laboratories in Aging Science

Cynthia Kenyon, PhD

Vice President of Aging Research, Calico Labs | Emeritus Professor, UCSF

If there is a single experiment that launched modern aging research, it was Cynthia Kenyon's 1993 discovery that mutations in the daf-2 gene could double the lifespan of C. elegans nematodes—and critically, that these worms remained youthful and healthy throughout their extended lives.

Published in Nature, Kenyon's finding demonstrated that aging was not an inevitable, immutable process but rather one governed by genetic pathways that could be manipulated. The daf-2 gene encodes an insulin/IGF-1 receptor, and mutations that reduce its activity activate the transcription factor DAF-16 (the worm equivalent of mammalian FOXO), triggering a cascade of protective mechanisms including enhanced stress resistance, improved protein quality control, and upregulated antioxidant defenses.

What made Kenyon's work revolutionary was the observation that these long-lived mutants were not merely surviving longer in a decrepit state—they were functionally younger. A 60-day-old daf-2 mutant moved with the vigor of a 20-day-old wild-type worm. This suggested that interventions might not just extend lifespan but compress morbidity, allowing organisms to remain healthy for a greater proportion of their lives.

The insulin/IGF-1 signaling pathway has since been found to regulate lifespan across species from yeast to flies to mice, making it one of the most evolutionarily conserved longevity pathways. Kenyon's work established C. elegans as a premier model organism for aging research and provided the conceptual foundation for nutrient-sensing interventions including caloric restriction and pharmaceutical targeting of related pathways.

Since joining Calico in 2014, Kenyon has continued to explore the molecular mechanisms that could translate these findings into human therapeutics. In a 2023 lecture at UC Santa Barbara, she emphasized that "we can slow our biological clocks" through understanding the molecular components of aging—a statement backed by three decades of mechanistic research.

Leonard Guarente, PhD

Novartis Professor of Biology, MIT | Co-founder, Elysium Health

Leonard Guarente established the connection between sirtuins and aging through his groundbreaking work in the 1990s identifying SIR2 as a longevity gene in yeast. His laboratory was the first to demonstrate that SIR2 and related sirtuin proteins function as NAD⁺-dependent enzymes, forging the initial link between cellular energy metabolism and the aging process.

Guarente showed that increased SIR2 expression extended yeast replicative lifespan by promoting genomic stability—specifically by silencing repetitive DNA sequences near telomeres and preventing the formation of toxic extrachromosomal rDNA circles. When his lab demonstrated that caloric restriction's lifespan extension required SIR2, it suggested a unified mechanism: reduced nutrient availability increases NAD⁺/NADH ratios, activating sirtuins and triggering a coordinated stress response.

Over four decades at MIT, Guarente's research has expanded to mammalian systems, demonstrating that SIRT1 (the mammalian SIR2 ortholog) regulates metabolism, circadian rhythms, mitochondrial biogenesis, and responses to cellular stress. His work revealed that NAD⁺ levels naturally decline with age, compromising sirtuin function—a finding that has spawned an entire field investigating NAD⁺ precursor supplementation.

In 2014, Guarente co-founded Elysium Health to commercialize NAD⁺ boosting supplements based on this research. The company's scientific advisory board includes eight Nobel laureates, and its flagship product combines nicotinamide riboside (an NAD⁺ precursor) with pterostilbene (a sirtuin activator). While this commercial involvement has drawn criticism—some scientists question whether researchers should profit from their own discoveries—Guarente maintains that rigorous clinical validation justifies the approach.

Recent 2025 coverage confirms that the longevity field has "moved from the fringes to science's hot center," attracting billions in investment. Guarente's work connecting NAD⁺ biology to sirtuin function remains foundational to understanding how metabolic interventions might slow aging.

Shinya Yamanaka, MD, PhD

Director, Center for iPS Cell Research and Application (CiRA), Kyoto University | Senior Investigator, Gladstone Institutes

Shinya Yamanaka's 2006 discovery of induced pluripotent stem cells (iPSCs) earned him the 2012 Nobel Prize in Physiology or Medicine and fundamentally altered our understanding of cellular identity and aging. By introducing just four transcription factors—Oct3/4, Sox2, Klf4, and c-Myc, now collectively known as "Yamanaka factors"—Yamanaka demonstrated that adult somatic cells could be reprogrammed into a pluripotent state capable of differentiating into any cell type.

While the original application focused on regenerative medicine and disease modeling, the aging research community quickly recognized profound implications: if mature cells retain the epigenetic information necessary to return to a youthful, pluripotent state, then aging might represent an epigenetic drift rather than irreversible genetic damage. This insight has catalyzed research into partial cellular reprogramming as an anti-aging strategy.

The key innovation for longevity applications came from researchers who discovered that transient, partial expression of Yamanaka factors—insufficient to fully dedifferentiate cells but enough to reset epigenetic marks—could rejuvenate cells without erasing their terminal identity. Studies in mice have shown that partial reprogramming can restore youthful gene expression patterns, extend telomeres, improve mitochondrial function, reduce oxidative stress, and enhance tissue regeneration without forming teratomas (the major safety concern with full pluripotency).

In groundbreaking 2024-2025 developments, researchers leveraged OpenAI's GPT-4b model to design novel, significantly enhanced variants of Yamanaka factors. These AI-optimized proteins achieved greater than 50-fold higher expression of stem cell reprogramming markers compared to wild-type controls and demonstrated enhanced DNA damage repair capabilities—indicating higher rejuvenation potential. This represents a fusion of AI and aging research that could accelerate therapeutic development.

Research published in 2025 showed that cellular reprogramming techniques can protect neurons from inflammation and cell death, with potential applications for neurodegenerative diseases. Companies including Altos Labs, Calico, and Retro Biosciences are now pursuing reprogramming-based therapies, making Yamanaka's discovery a cornerstone of next-generation anti-aging interventions.

David Sinclair, PhD, AO

Professor of Genetics, Harvard Medical School | Co-Director, Paul F. Glenn Center for Biology of Aging Research

David Sinclair is perhaps the most visible and controversial figure in modern aging research. His work has established fundamental connections between NAD⁺ metabolism, sirtuin activation, and aging, while his public advocacy and commercial ventures have made him a polarizing figure in the field.

Sinclair's early career focused on yeast aging and the role of SIR2 in genomic stability. His 2003 Nature paper claiming that resveratrol activated sirtuins and extended lifespan in yeast sparked enormous interest—and subsequent controversy when other labs struggled to replicate the direct activation mechanism. Despite this setback, the broader principle that sirtuin activators could have anti-aging effects has been validated through alternative mechanisms.

More recently, Sinclair's lab has focused on NAD⁺ decline as a central driver of aging. They demonstrated that NAD⁺ levels fall with age across multiple tissues, that this decline impairs mitochondrial function and DNA repair, and that supplementation with NAD⁺ precursors (particularly nicotinamide mononucleotide or NMN) can restore youthful cellular function in mice. His "Mitochondrial Oasis Hypothesis" proposes that leakage of NAD⁺ from mitochondria contributes to aging and memory loss.

Sinclair has also been instrumental in developing the Information Theory of Aging, which posits that aging results from epigenetic information loss rather than DNA damage accumulation. This theory, detailed in his 2019 book Lifespan: Why We Age—and Why We Don't Have To, suggests that cells retain a backup copy of youthful epigenetic information that could theoretically be restored through interventions like cellular reprogramming.

In 2024-2025, Sinclair's group has incorporated AI techniques to accelerate cellular reprogramming research. They demonstrated that age-reversal technology can protect neurons from inflammation and cell death in mice—findings published in Cell Reports. Sinclair predicts that age-reversing pills targeting specific genes will be available within 10 years, with clinical trials of NAD⁺-boosting molecules already underway.

Sinclair's commercial involvement—he co-founded companies including Sirtris Pharmaceuticals (acquired by GlaxoSmithKline), Metro Biotech, and InsideTracker—has drawn criticism from scientists who question whether academic researchers should profit from their discoveries. His aggressive public advocacy and sometimes overstated claims have also generated pushback within the gerontology community.

Nevertheless, Sinclair's work has been highly influential in establishing NAD⁺ metabolism and sirtuin activation as major therapeutic targets, and his public communication has raised awareness of aging research far beyond academic circles.

Judith Campisi, PhD (1948–2024)

Professor, Buck Institute for Research on Aging | Senior Scientist, Lawrence Berkeley National Laboratory

The field of aging research lost one of its most influential voices when Judith Campisi passed away on January 19, 2024, following a prolonged illness. Her contributions to our understanding of cellular senescence and its role in aging and disease were transformative and continue to shape therapeutic development.

Campisi's work established that cellular senescence—the state in which cells permanently exit the cell cycle—plays a complex, antagonistic role in aging. While senescence is initially protective, preventing damaged cells from becoming cancerous, the accumulation of senescent cells over time contributes to tissue dysfunction, chronic inflammation, and age-related pathology.

In 1999, Campisi and colleagues identified senescence-associated β-galactosidase as the first marker for senescent cells in living tissue, providing researchers with a crucial tool for detecting and studying these cells. This breakthrough enabled subsequent investigations into senescent cell biology and therapeutic targeting.

Her most influential discovery came in 2008 with the identification of the senescence-associated secretory phenotype (SASP)—the observation that senescent cells secrete a complex mixture of pro-inflammatory cytokines, growth factors, proteases, and other bioactive molecules that profoundly alter their tissue microenvironment. The SASP explained how a relatively small number of senescent cells could have outsized effects on tissue function and provided mechanistic insight into how cellular senescence contributes to the chronic inflammation characteristic of aging (often termed "inflammaging").

This breakthrough led Campisi to propose that selective elimination of senescent cells could represent a novel therapeutic strategy against age-related diseases. She coined the term "senolytics" to describe agents capable of inducing senescent cell death while sparing normal cells—a concept that has since spawned an entire therapeutic field.

Campisi's laboratory also developed the 3MR mouse model in 2014, which allows researchers to track and selectively eliminate senescent cells in living animals. Using this model, her team demonstrated that senescent cells play essential roles in processes like wound healing (where they are transiently beneficial) but cause tissue dysfunction when they persist chronically. The direct demonstration that senescent cell elimination could delay age-related pathology validated senolytics as a therapeutic approach.

Throughout her career, Campisi published nearly 500 papers that have been cited approximately 105,000 times—a testament to her profound influence on the field. Beyond research, she played pivotal roles in establishing the NIH Cellular Senescence Network (SenNet) and championed the Bay Area Aging Network, including a renowned T32 training grant connecting UCSF, UC Berkeley, Stanford, and the Buck Institute.

At a February 2024 Celebration of Life, colleagues and friends from around the world gathered to share testimonials highlighting Campisi's impact on both individuals and the field. Her legacy endures through the continued exploration of cellular senescence and senolytic therapeutics, research directions she pioneered and championed until the end of her life.

Jan van Deursen, PhD

Professor of Biochemistry and Molecular Biology, Mayo Clinic

Jan van Deursen provided the definitive proof that senescent cells are causally implicated in age-related pathology through his development of the INK-ATTAC transgenic mouse model. This elegant genetic system allowed, for the first time, the selective elimination of senescent cells in living mammals—and the results were striking.

Van Deursen joined Mayo Clinic in 1999 after pioneering work in gene targeting and knockout mouse technology. His transition to aging research began with studies of a mouse model of accelerated aging (BubR1 hypomorphism), in which senescent cells accumulated prematurely alongside progeroid symptoms.

The INK-ATTAC (Inducible Elimination of p16^Ink4a-positive cells by Apoptosis Through Targeted Activation of Caspase) transgene uses the promoter of p16^Ink4a—a canonical senescence marker—to drive expression of a drug-inducible caspase. When mice carrying this transgene are treated with the small molecule AP20187, p16-expressing senescent cells undergo apoptosis while other cells remain unaffected.

In landmark 2011 and 2016 publications in Nature, van Deursen's team showed that:

• In progeroid mice, clearing senescent cells delayed onset of age-related pathologies
• In naturally aged wild-type mice, lifelong senescent cell clearance (starting at one year of age) extended median lifespan in both males and females across two genetic backgrounds
• Senescent cell clearance improved health in adipose tissue, skeletal muscle, and eye
• Even late-life clearance (starting at 18 months) attenuated progression of already-established age-related disorders
• These benefits occurred without apparent toxicity or increased cancer incidence

These findings were revolutionary because they demonstrated causality: senescent cells don't just correlate with aging—they actively drive it. The fact that even late-life clearance provided benefits suggested therapeutic windows that could apply to elderly humans.

Van Deursen's work also showed that senescent cell clearance prevents tau-dependent pathology and cognitive decline in mouse models of neurodegeneration, and that whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment. These findings extended the senescent cell hypothesis beyond traditional aging phenotypes to neurodegenerative disease.

The INK-ATTAC model remains a gold standard tool for senescence research and has inspired numerous pharmaceutical efforts to develop senolytic drugs that could achieve similar clearance in humans without genetic manipulation.

James Kirkland, MD, PhD

Director, Robert and Arlene Kogod Center on Aging, Mayo Clinic

James Kirkland translated the senescent cell hypothesis into pharmacological reality by discovering the first senolytic drugs and leading the clinical trials that demonstrated their potential in humans. His hypothesis-driven approach to drug discovery has established senolytics as one of the most promising near-term anti-aging interventions.

Kirkland's strategy was elegant in its simplicity: senescent cells are inherently stressed, having activated multiple pro-survival pathways to resist their own pro-apoptotic microenvironment. If these survival pathways could be transiently disrupted, senescent cells might undergo apoptosis while normal cells—which don't rely as heavily on these pathways—would survive.

Testing this hypothesis, Kirkland's team screened compounds targeting known pro-survival networks and identified the first generation of senolytics. Dasatinib, a tyrosine kinase inhibitor approved for chronic myeloid leukemia, proved effective against senescent preadipocytes and endothelial cells. Quercetin, a naturally occurring flavonoid found in apple peels, worked against senescent endothelial cells and bone marrow stromal cells. The combination (D+Q) showed synergistic effects across multiple cell types.

Preclinical studies in 2015-2018 demonstrated that D+Q treatment in aged mice produced remarkable benefits: improved physical function, reduced frailty, enhanced cardiovascular health, and—critically—increased lifespan when treatment began in old age. These findings suggested that senolytics might compress morbidity rather than merely extending lifespan.

Kirkland rapidly advanced senolytics into human trials. A 2019 pilot study in patients with diabetic kidney disease showed that a short course of D+Q (three days of oral administration) significantly decreased senescent cell burden in adipose tissue—the first demonstration that senolytics could eliminate senescent cells in humans. Importantly, the treatment was well-tolerated, with no serious adverse events.

Subsequent trials have tested senolytics in idiopathic pulmonary fibrosis (a devastating age-related lung disease), osteoarthritis, frailty, and most recently, Alzheimer's disease. A March 2025 publication in EBioMedicine reported results from a trial of D+Q in older adults with Alzheimer's, extending senolytic research into neurodegenerative disease.

Beyond D+Q, Kirkland's team has characterized other senolytic compounds including fisetin (another flavonoid with senolytic properties) and navitoclax (a BCL-2 family inhibitor). Each compound has distinct cell-type specificity, suggesting that combination approaches might achieve more comprehensive senescent cell clearance.

Kirkland's work has established key principles for senolytic therapy: short treatment courses (rather than continuous dosing), tolerance monitoring, and selection of indications where senescent cell burden is elevated. His clinical trial designs have become templates for the field, and his research continues to guide therapeutic development in what has become one of the most clinically advanced areas of aging intervention.

Steve Horvath, PhD

Principal Investigator, Altos Labs | Professor Emeritus, UCLA

Steve Horvath revolutionized aging research by developing the first accurate epigenetic clocks—algorithms that use DNA methylation patterns to predict biological age with unprecedented precision. His work has provided the field with objective, quantitative biomarkers that can measure aging rate and assess potential interventions.

Horvath's 2013 publication describing his first-generation epigenetic clock marked a watershed moment. By analyzing DNA methylation at 353 CpG sites across the genome, he created a predictor that could estimate chronological age within 3.6 years across multiple tissues and cell types. Critically, deviations from chronological age—"epigenetic age acceleration"—predicted mortality risk, disease incidence, and physical function independently of chronological age.

What made Horvath's approach revolutionary was its pan-tissue applicability. Unlike previous aging biomarkers that worked only in specific cell types, Horvath's clock could estimate age in blood, brain, liver, kidney, muscle, and even saliva. This suggested the existence of a universal epigenetic aging process operating across all cell types—a finding with profound implications for our understanding of systemic aging.

Horvath has since developed multiple refined clocks for specific applications:

• PhenoAge (developed with Morgan Levine): optimized to predict phenotypic age and mortality risk
• GrimAge: predicts time to death and healthspan with high accuracy
• Pan-mammalian clocks (2023): capable of estimating age across all mammalian species, enabling comparative aging research
• Lifespan predictors: epigenetic signatures that predict maximum lifespan and gestation time across mammals

In 2024, Horvath and colleagues published theoretical work proposing fundamental equations linking methylation dynamics to maximum lifespan in mammals, providing a mathematical framework for understanding how epigenetic aging rates scale with species longevity.

Since joining Altos Labs, Horvath has continued advancing epigenetic clock technology while exploring their application in identifying and validating anti-aging interventions. A January 2025 publication in Genome Biology discussed emerging computational challenges in epigenetic aging clocks, indicating ongoing methodological refinement.

Horvath's clocks have become essential tools throughout aging research, providing outcome measures for clinical trials, enabling mechanistic studies of aging hallmarks, and quantifying the effects of interventions from caloric restriction to pharmacological treatments. The field's ability to measure biological age objectively has accelerated dramatically since Horvath's foundational work.

Morgan Levine, PhD

Founding Principal Investigator, Altos Labs

Morgan Levine has been instrumental in translating epigenetic clocks into clinically meaningful biomarkers that predict health outcomes and guide interventional strategies. Her work bridges the gap between molecular aging signatures and real-world health risks.

While completing her PhD at UCLA, Levine began collaborating with Steve Horvath on epigenetic aging. Her major independent contribution came in 2018 with the development of PhenoAge—an epigenetic clock specifically optimized to predict phenotypic aging and mortality rather than simply chronological age.

PhenoAge was constructed using a two-step approach: first, Levine identified a combination of nine clinical biomarkers (albumin, creatinine, glucose, C-reactive protein, lymphocyte percent, mean cell volume, red cell distribution width, alkaline phosphatase, and white blood cell count) that together predicted mortality risk better than chronological age. Then, she trained an epigenetic predictor to estimate this "phenotypic age" from DNA methylation patterns.

The result was remarkably powerful: each one-year increase in PhenoAge above chronological age was associated with a 9% increase in all-cause mortality risk. PhenoAge outperformed chronological age in predicting cardiovascular disease, cancer, Alzheimer's disease, and physical function decline. Importantly, it captured aging differences across diverse populations, working equally well across ethnicities and socioeconomic groups.

What makes PhenoAge particularly valuable for intervention research is its sensitivity to lifestyle factors and therapeutic interventions. Studies have shown that PhenoAge acceleration is influenced by diet, exercise, sleep, stress, and various medications—suggesting it captures modifiable aspects of biological aging rather than fixed genetic trajectories.

Since joining Altos Labs as a founding principal investigator, Levine has continued refining biological age assessment and exploring how epigenetic reprogramming might reverse age-related methylation changes. Her work contributes to Altos Labs' ambitious goal of developing cellular rejuvenation therapies based on understanding and reversing the fundamental mechanisms of aging.

Levine is also a prominent science communicator, having appeared on numerous podcasts including the FoundMyFitness podcast with Rhonda Patrick, where she discussed the epigenetics of age acceleration and whether we can change the pace of aging through interventions. Her research continues to shape how the field measures and targets biological aging in both research and clinical contexts.

Carlos López-Otín, MD, PhD

Professor of Biochemistry and Molecular Biology, University of Oviedo, Spain

Carlos López-Otín has provided the conceptual architecture that organizes our understanding of aging mechanisms through his work establishing and expanding the Hallmarks of Aging framework. These hallmarks serve as a roadmap for both research priorities and therapeutic development across the field.

The original 2013 Cell paper "The Hallmarks of Aging," co-authored with Manuel Serrano, Maria Blasco, Linda Partridge, and Guido Kroemer, identified nine fundamental features that characterize biological aging across species. These hallmarks provided a systematic way to think about aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

The framework distinguished between primary hallmarks (causes of cellular damage), antagonistic hallmarks (responses that are initially beneficial but become harmful when chronic or excessive), and integrative hallmarks (consequences that directly drive functional decline). This hierarchy helped researchers understand how different aging mechanisms interact and cascade.

Ten years later, in 2023, López-Otín and colleagues published "Hallmarks of aging: An expanding universe" in Cell, acknowledging that aging research had advanced sufficiently to warrant expansion. They added three new hallmarks: disabled macroautophagy, chronic inflammation (inflammaging), and dysbiosis (alterations in the microbiome). The authors explicitly noted that "the list was not conceived as closed," inviting continued refinement as understanding deepens.

Each hallmark has spawned dedicated research programs and therapeutic approaches:

• Genomic instability: DNA repair enhancement strategies
• Telomere attrition: Telomerase activation approaches
• Epigenetic alterations: Reprogramming therapies and epigenetic modifiers
• Loss of proteostasis: Chaperone activation, proteasome enhancement
• Deregulated nutrient-sensing: mTOR inhibition, AMPK activation, sirtuin modulation
• Mitochondrial dysfunction: NAD⁺ restoration, mitochondrial-targeted antioxidants
• Cellular senescence: Senolytic drugs
• Stem cell exhaustion: Regenerative medicine, niche restoration
• Altered intercellular communication: Anti-inflammatory interventions, young blood factors
• Disabled macroautophagy: Autophagy-inducing compounds like rapamycin
• Chronic inflammation: Inflammasome inhibitors, anti-inflammatory biologics
• Dysbiosis: Microbiome modulation, prebiotics, probiotics

The framework has proven remarkably durable while remaining flexible enough to incorporate new discoveries. Some researchers have proposed additional candidate hallmarks—including mechanobiology and cellular hypertrophy—though these remain under discussion rather than formally adopted.

Beyond providing structure, the Hallmarks framework has facilitated translational research by identifying clear intervention points. Rather than viewing aging as an amorphous process, researchers can now target specific mechanisms with measurable outcomes. López-Otín's conceptual contribution has been as valuable as many experimental discoveries, shaping how the entire field thinks about aging biology.

Nir Barzilai, MD

Director, Institute for Aging Research, Albert Einstein College of Medicine | Scientific Director, American Federation for Aging Research (AFAR)

Nir Barzilai has been a tireless advocate for treating aging itself as a therapeutic target rather than addressing age-related diseases individually. His leadership of the TAME (Targeting Aging with Metformin) trial represents a landmark effort to convince regulators that aging can and should be treated as a condition in its own right.

Barzilai's research career has focused on exceptional human longevity, particularly the genetic and physiological factors that distinguish centenarians from average-aging individuals. His studies of Ashkenazi Jewish centenarians identified genetic variants associated with extreme longevity, healthier lipid profiles, larger LDL particle size, and better insulin sensitivity—providing clues about biological pathways that promote healthy aging in humans.

This work revealed that centenarians don't just live longer—they compress morbidity into the final years of life, remaining functionally independent and cognitively intact into their 90s and beyond. The "SuperAgers" studies demonstrated that cognitive function in these individuals resembles that of people 20-30 years younger, suggesting that slowing brain aging is achievable.

TAME emerged from Barzilai's conviction that we should test whether drugs can slow multiple age-related conditions simultaneously rather than treating each disease separately. Metformin, a first-line diabetes medication with an excellent safety profile and hints of broader health benefits, was an ideal candidate. Observational studies showed that diabetics taking metformin lived longer than non-diabetic controls and had reduced cancer, cardiovascular disease, and dementia risk—suggesting effects beyond glucose control.

Designed to enroll 3,000 participants aged 65-79 across approximately 14 U.S. centers, TAME will measure time to a composite outcome including cardiovascular events, cancer, dementia, and mortality. The trial asks whether metformin can delay the onset of multiple age-related conditions—a question that has never been formally tested in humans.

Crucially, TAME is structured to convince the FDA that aging itself can be a therapeutic target. If successful, it would establish a regulatory pathway for future longevity drugs, transforming aging research from a purely academic pursuit into a recognized clinical field.

As of 2025, TAME remains only partially funded despite decades of effort. In August 2025, Barzilai reported that TAME is now being handled within ARPA-H (Advanced Research Projects Agency for Health), potentially providing the substantial funding needed to complete the trial. He has also noted that Eli Lilly plans to conduct a TAME-like study with their GLP-1 agonist, validating the approach of testing drugs against composite aging outcomes.

Recent evidence continues to accumulate supporting metformin's effects: a paper in the Journal of Gerontology showed that people taking metformin are twice as likely to reach age 90 as other people with diabetes. Barzilai summarizes: "There are 34,731 papers about metformin... most of them are good; the positive evidence is mounting."

Through AFAR, Barzilai has mentored numerous young investigators and championed increased funding for aging research. His advocacy work—including congressional testimony and public outreach—has been instrumental in elevating geroscience from a niche field to a funding priority. See related work on metformin's longevity effects and the broader clinical trials landscape.

Matt Kaeberlein, PhD

Professor, University of Washington | Co-Director, Dog Aging Project

Matt Kaeberlein has bridged the gap between laboratory aging research and real-world translational studies through his leadership of the Dog Aging Project—an ambitious study leveraging companion dogs to understand aging and test interventions in a large mammal with naturally occurring age-related diseases.

Kaeberlein's early research focused on yeast aging, where he contributed to understanding how caloric restriction, mTOR signaling, and mitochondrial function influence lifespan. He demonstrated that inhibition of TOR (target of rapamycin) extends lifespan across evolutionarily distant species from yeast to flies to mice, establishing mTOR as one of the most conserved longevity pathways.

This work naturally led to interest in rapamycin, an mTOR inhibitor FDA-approved for immunosuppression. Studies in mice showed that rapamycin extended lifespan even when treatment began in old age—one of the few interventions to show this property. However, translating these findings to humans presented challenges: the doses required for immunosuppression cause side effects, and conducting lifespan studies in humans is impractical.

Enter the Dog Aging Project. Companion dogs offer unique advantages as an aging model: they share human environments (including environmental exposures and healthcare access), develop similar age-related diseases (cancer, heart disease, cognitive decline, arthritis), have relatively short lifespans (allowing completion of longitudinal studies within a decade), and are large enough to undergo the same diagnostic procedures as humans. Moreover, dog owners are highly motivated to participate in health studies involving their pets.

The Dog Aging Project encompasses two components: a massive longitudinal study tracking health and aging in tens of thousands of companion dogs across diverse breeds and environments, and the TRIAD (Test of Rapamycin In Aging Dogs) clinical trial testing whether rapamycin can extend healthspan and lifespan in middle-aged to senior dogs.

TRIAD enrolled healthy, medium-to-large breed dogs and administered either rapamycin or placebo, monitoring functional measures of aging and age-related disease burden. The study design leveraged rapamycin's established safety profile and the evidence that it extends lifespan and improves health when initiated in middle age or administered intermittently.

Results from TRIAD, published in December 2024 and early 2025, represent the first rigorous test of rapamycin's effects on aging in a large mammal. In December 2024, tech entrepreneurs pledged $2.5 million to expand TRIAD to include more study locations and enroll additional dogs—demonstrating private sector confidence in the approach.

Kaeberlein's work has been featured prominently in mainstream media, including National Geographic (December 2024) and NPR, where he discussed rapamycin's possible benefits for extending healthspan. His ability to communicate complex science to general audiences has raised public awareness of aging research.

Beyond dogs, Kaeberlein is an advocate for using lifespan and healthspan extension as explicit goals of biomedical research. He has argued that focusing on individual age-related diseases—while ignoring their common underlying cause (aging itself)—is inefficient compared to targeting aging mechanisms directly. The Dog Aging Project provides a proof-of-concept for this approach in a mammalian system where results can inform human applications within reasonable timeframes.

Luigi Fontana, MD, PhD

Professor of Medicine and Nutrition, University of Sydney | Formerly: Washington University School of Medicine

Luigi Fontana has been instrumental in translating caloric restriction research from model organisms to humans, demonstrating that sustained calorie reduction produces profound cardiometabolic benefits that may slow biological aging in people.

Caloric restriction (CR)—reducing calorie intake by 20-40% without malnutrition—remains the most robust non-genetic intervention for extending lifespan across species from yeast to primates. However, whether CR slows aging in humans remained uncertain until Fontana and colleagues conducted systematic studies in both practitioners of voluntary CR and randomized controlled trials.

Fontana's observational studies of CR Society members—individuals who had voluntarily restricted calories by 25-30% for 3-15 years—revealed remarkable cardiovascular health. These individuals had lower blood pressure, more favorable lipid profiles, reduced inflammation markers, improved insulin sensitivity, and arterial compliance resembling that of people decades younger. Their cardiac function suggested biological ages substantially below their chronological ages.

These findings provided proof-of-principle but left open questions about feasibility, safety, and mechanisms. Could typical humans maintain caloric restriction? Would benefits require lifelong adherence? What metabolic pathways mediated effects?

Fontana was a key investigator in CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), the largest and most rigorous controlled trial of sustained caloric restriction in humans. CALERIE Phase 2 enrolled 218 healthy, non-obese adults aged 21-50 at three U.S. clinical centers, randomizing them to either 25% calorie restriction or ad libitum diet for two years.

Published between 2015-2019, CALERIE demonstrated that sustained CR in humans produces multiple cardiometabolic benefits:

• Significant improvements in cardiometabolic risk factors including insulin sensitivity, blood pressure, and C-reactive protein
• Reduction in metabolic syndrome risk scores
• Favorable changes in body composition, with losses primarily from visceral fat
• Reduced oxidative stress assessed by urinary F2-isoprostanes
• Lower levels of IGF-1 and other growth factors associated with aging and cancer risk

Importantly, benefits scaled linearly with degree of weight loss—suggesting dose-dependent effects on biological aging. Participants who achieved greater calorie restriction showed larger improvements.

A February 2025 publication describing the CALERIE Genomic Data Resource provided researchers with access to comprehensive molecular data (genomics, transcriptomics, metabolomics) from all 218 participants throughout the trial. This dataset enables mechanistic investigations into how caloric restriction affects aging pathways at the molecular level.

Fontana's work has also explored the distinction between caloric restriction and protein restriction, showing that limiting protein intake (particularly methionine and branched-chain amino acids) may recapitulate some benefits of overall CR. This finding has implications for designing more tolerable dietary interventions.

While CALERIE demonstrated feasibility and safety, it also highlighted challenges: achieving 25% restriction requires substantial effort and discipline, and many participants fell short of the target reduction. This has motivated research into CR mimetics—drugs that produce similar metabolic effects without requiring actual calorie reduction. Fontana's human studies provide benchmarks against which such mimetics can be compared. Related research is covered in caloric restriction mechanisms.

Aubrey de Grey, PhD

LEV (Longevity Escape Velocity) Foundation

Aubrey de Grey introduced an engineering-based framework for aging, treating it as a problem of accumulated damage that can be identified, categorized, and repaired. His SENS (Strategies for Engineered Negligible Senescence) framework, detailed in his 2007 book Ending Aging, categorizes aging damage into seven types including cell loss, senescent cell accumulation, mitochondrial mutations, intra- and extracellular aggregates, and extracellular matrix cross-linking.

For each damage type, de Grey proposed specific repair strategies. Several have since gained significant traction: senolytics (now a validated therapeutic approach) directly target senescent cells, and mitochondrial gene therapy approaches are under active development. Through SENS Research Foundation and subsequently the LEV Foundation, de Grey has funded early-stage, high-risk projects that conventional funding agencies often rejected — including pioneering work on senescent cell clearance, mitochondrial allotopic expression, and glucosepane cross-link breakers.

De Grey continues this work through the LEV Foundation, which funds research aimed at achieving "longevity escape velocity" — the point at which life expectancy gains outpace chronological aging. The foundation supports damage-repair research across multiple hallmarks of aging.