Anti-Aging Drugs: New Criteria to Identify Treatments That Really Work

Table of Contents

• Key Points
• The Aging Challenge: Why Scientists Are Searching for Anti-Aging Drugs
• What Is a Geroprotector?
• Why Haven't Anti-Aging Drugs Reached the Market Yet?
• How the Researchers Built Their Evaluation System
• Primary Selection Criteria: The "Must-Have" Requirements
• Secondary Selection Criteria: The "Strongly Recommended" Requirements
• Top Candidate Geroprotectors Identified by the Authors
• Clinical Implications: What This Means for Patients
• Limitations: What This Study Couldn't Prove
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Over 200 substances extend lifespan in animals, but none are approved as anti-aging treatments for humans.
• The proposed system has five primary criteria: increased lifespan, biomarker improvement, acceptable toxicity, minimal side effects, and better quality of life.
• Ten candidate geroprotectors, including metformin, acarbose, and glucosamine, appear to meet all main criteria.
• The goal is healthspan—the disease-free period of life—not just longer lifespan.

The Aging Challenge: Why Scientists Are Searching for Anti-Aging Drugs

Aging is the single greatest risk factor for most of the chronic diseases that dominate modern medicine: cancer, type II diabetes, atherosclerosis (hardening of the arteries), hypertension (high blood pressure), heart attack, stroke, and neurodegenerative diseases such as Alzheimer's and Parkinson's.

The coming decades will bring a massive shift in the age of the world's population, with major social and economic consequences. The authors note that in developed countries, the geroscience concept — which aims to extend the healthy state of the human body rather than just treat individual diseases — is likely to become a key paradigm of biomedicine in the coming decades.

The good news? In animal models, treatments that extend lifespan often also protect against these chronic diseases. Researchers believe the same approach may work in humans, potentially preventing or at least delaying many age-related conditions with a single intervention.

What Is a Geroprotector?

The concept of geroprotectors dates back more than a century. The terms "geroprotector" and "gerontology" were first introduced by the famous scientist Ilya Mechnikov in 1910. The word literally translates as "protecting against aging" — in essence, deterring the aging process and prolonging life.

The field has exploded in recent years. In a 2009 review, researchers Kapoor and colleagues listed 24 known geroprotectors. Today, according to the Geroprotectors.org database, more than 200 substances are classified as geroprotectors, each reported to slow aging or increase lifespan in organisms ranging from yeast and nematode worms to fruit flies and rodents.

Various synonyms appear in the scientific literature, including "anti-aging drugs," "longevity therapeutics," "gerosuppressant," and "aging-suppressant." The authors also propose distinct terms for substances at different stages of validation: a potential or candidate geroprotector is a substance that shows positive effects on aging mechanisms or age-related disease risk but lacks direct experimental evidence of lifespan extension.

For example, dasatinib — a drug in the new class of "senolytics" that selectively kill senescent ("zombie") cells — has shown notable senolytic potential, but its effects on lifespan are not yet known. Under the proposed framework, it would be considered a candidate geroprotector rather than a confirmed one.

Why Haven't Anti-Aging Drugs Reached the Market Yet?

Despite the impressive rate of discovery, not a single geroprotector has yet reached the pharmaceutical market as a recognized intervention specifically targeting the aging process. The authors identify four major reasons:

1. No unified scientific concept of aging. The primary triggers of aging are still poorly understood, which means the molecular targets for candidate drugs are often unknown.
2. No comprehensive system of human aging biomarkers. Biomarkers (measurable biological indicators) are critical for translating results from simple model organisms to preclinical studies and eventually to human clinical trials.
3. Aging is not recognized as a disease. Regulators and pharmaceutical companies are reluctant to invest in drugs targeting a condition that isn't officially classified as a disease or syndrome.
4. No consensus on criteria. The scientific community cannot agree on what counts as a geroprotector, how to select candidates, how to classify them, or how to rate their effectiveness. This lack of standardization hampers progress at every stage.

How the Researchers Built Their Evaluation System

One of the most promising avenues for finding new geroprotectors is bioinformatics. According to the GenAge database, there are 1,825 genes whose knockout, knockdown, or overexpression is known to increase lifespan. The authors argue that a purposeful search for substances that affect these genes and their encoded proteins will significantly expand the pool of potential geroprotectors.

An important insight from comparative biology: evidence shows that many key causes and mechanisms of aging are ancient and evolutionarily conserved — meaning they're shared across species separated by hundreds of millions of years of evolution. This means that treatments that work in worms or flies have a reasonable chance of working in humans.

However, comparing results across studies is currently very difficult. Researchers use different experimental conditions, different model organisms, and different genetic backgrounds within species — all of which complicate interpretation. Creating a standardized system of criteria is therefore essential, not just for scientists but ultimately for patients who need to know which treatments are worth pursuing.

A key concern driving this work is that simply extending lifespan isn't enough. Some long-lived mutant worms (C. elegans) have been shown to have a poorer quality of life, with impaired functional capabilities. The real goal for translation into humans should be an increase in healthspan — the fully active, disease-free period of life.

The authors divided their proposed criteria into two groups: primary (must be met unconditionally) and secondary (can accelerate discovery, reduce cost, or establish whether results will translate to humans).

Primary Selection Criteria: The "Must-Have" Requirements

The primary criteria represent non-negotiable requirements for any candidate geroprotector. These are the five core qualifications:

1. Increased Lifespan

This is "undoubtedly the most significant main criterion." At the population level, increased lifespan shows up as reduced mortality. In an ideal scenario, positive changes appear across all characteristics of the survival curve: mean lifespan, median lifespan, maximum lifespan, age of 90% mortality, and the rate of aging itself.

Researchers often use a measure called mortality rate doubling time (MRDT) to quantify the rate of aging. MRDT is derived from the Gompertz equation — the mathematical formula that describes mortality rates in populations — and is calculated as MRDT = 0.693/G, where G is the exponential (Gompertz) mortality rate coefficient. An increase in MRDT reflects a decrease in the rate of aging.

2. Amelioration of Human Aging Biomarkers

Since human lifespan studies are extremely lengthy and costly, biomarkers offer a practical shortcut. Biomarkers of aging are molecular, cellular, and physiological parameters that demonstrate reproducible changes with age. An ideal geroprotector should reverse these biomarkers to a younger state or at least slow their age-related progression.

Good biomarkers should be minimally invasive, reproducible, and reflective of major aging mechanisms. The most comprehensive list of human aging biomarkers is available in the Digital Ageing Atlas (ageing-map.org). Examples of biomarker improvements include:

• In cell culture studies: expression of telomere-related genes, beta-amyloid-lowering effects, low levels of advanced glycation end products and oxidative damage, reduced levels of lipofuscin (a cellular "aging pigment")
• In human clinical trials: prevention of neurodegeneration, reduced hypertension, lowered blood glucose, anti-inflammatory effects, triglyceride lowering, improved insulin sensitivity, better immune function in the elderly, and delayed skin aging

One notable study cited by the authors evaluated a collection of candidate biomarkers longitudinally in a relatively young population. This research developed a criterion for predicting biological age that was predictive of functional parameters in 38-year-olds — suggesting that biomarker-based testing of geroprotectors could be greatly accelerated if validated across multiple human cohorts.

3. Acceptable Toxicity

Most geroprotectors only show preventive effects when used at relatively high concentrations over long periods. Evaluating toxicity typically involves studies in model organisms, following FDA guidelines. Key toxicity measures include:

• Acute toxicity, characterized by the median lethal dose (LD50) — the dose that kills half of the test animals
• Doses that are toxic to specific target organs
• Doses that induce carcinogenicity (cancer)
• Doses that reduce fertility
• Doses that increase germ cell mutagenicity (genetic damage to sperm or egg cells)

The acceptable safety margin should be substantial: the authors specify that there must be several orders of magnitude difference between the lifespan-extending dose and the toxic dose.

4. Minimal Side Effects at Therapeutic Dosage

Some substances that prolong lifespan in model animals come with serious side effects. Reported problems include dyslipidemia (abnormal blood fats), anemia, insulin resistance, increased susceptibility to infections, hypertension, and gastrointestinal disorders.

Because geroprotectors would ideally be used for many years — potentially decades — even mild side effects become a major concern. Over years of use, unwanted effects may reduce both quality of life and the effectiveness of the treatment. The authors emphasize that the number and severity of side effects should be minimal at the doses needed to achieve positive effects in humans.

5. Improving Health-Related Quality of Life

Aging brings decreased metabolic efficiency, reduced mental and physical activity, and a rising incidence of illness and disability. Potential geroprotectors should improve at least a subset of these parameters, including physical, mental, emotional, and social functioning.

Encouragingly, some geroprotectors are reported to stimulate cognitive function and show antidepressant-like effects when used in therapy — for instance, by preventing sleep disorders. The authors stress again that increasing lifespan at the cost of quality of life is not an acceptable tradeoff.

Secondary Selection Criteria: The "Strongly Recommended" Requirements

While not strictly mandatory, the following four secondary criteria can accelerate the identification of geroprotective properties, reduce research costs, and help establish whether results in animals will translate to humans.

1. Evolutionary Conservation of Target or Mechanism

If a drug targets a protein or pathway that has stayed essentially unchanged through evolution, its effects are more likely to carry over from simple organisms to mammals — and eventually humans. Several well-known geroprotectors hit highly conserved targets:

• TOR kinase, the target of rapamycin, is highly conserved from single-celled yeast all the way to humans
• AMPK, a central energy-sensing enzyme
• NF-κB, a master regulator of inflammation
• IGF-1R/Akt, a growth-signaling pathway

2. Reproducibility Across Different Model Organisms

A geroprotector that extends lifespan in multiple species — even without a known conserved target — deserves extra attention. Initial screening usually starts with short-lived invertebrates like worms and flies. If a drug also extends lifespan in a second invertebrate, the chances of human benefit rise, and data from mammals or human cells is even more valuable.

3. Simultaneous Influence on Multiple Age-Related Causes of Death

Since aging is an intrinsic process that enables many chronic diseases to develop, an ideal geroprotector should delay more than one age-associated pathology. Even today's geroprotective substances can be evaluated by their reported positive therapeutic effects on the major causes of human mortality (heart disease, cancer, respiratory disease, etc.).

4. Increase in Stress Resistance

A large body of evidence suggests that interventions that extend longevity also confer stress resistance — the ability to withstand adverse environmental conditions. Pathways linked to both stress resistance and longevity include:

• Insulin/IGF-1 signaling
• The TOR pathway
• NF-κB signaling
• DNA repair mechanisms
• Free radical detoxification
• Molecular chaperones (proteins that help other proteins fold correctly)
• Epigenetic control of gene expression

The authors reference a recent review by Epel and Lithgow suggesting that reduced stress resistance is a common feature of all nine hallmarks of aging, which include: loss of proteostasis (protein balance), epigenetic changes, genomic instability, telomere attrition, altered intercellular communication, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. The logic is that a true geroprotector should increase the body's resistance to stress as a sign that it activates longevity mechanisms.

Top Candidate Geroprotectors Identified by the Authors

Using their criteria, the authors analyzed published data and identified ten compounds that appear to satisfy all of the main criteria: acarbose, deprenyl, D-glucosamine, dihydroergocristine methanesulfonate, ellagic acid, fenofibrate, glutathione, metformin, spermidine, tyrosol, and vinpocetine. These are suggested as tractable candidates for human interventions.

Here's what the evidence shows for several of the most well-studied compounds:

Acarbose

Acarbose is an alpha-glucosidase inhibitor — a drug already approved for treating type 2 diabetes. It works by slowing the digestion of carbohydrates in the gut. In studies, male UM-HET3 mice treated with acarbose had a 22% longer lifespan. It has acceptable acute toxicity and is already widely used in humans with a well-established safety profile.

Metformin

Metformin is one of the most widely prescribed diabetes drugs in the world. Studies have shown it can reduce diabetes-related and all-cause mortality, heart attacks, and any diabetes-related endpoint in individuals with type 2 diabetes. Based on this evidence, scientists have launched a new clinical trial to investigate whether metformin can also reduce mortality in healthy adults (ClinicalTrials.gov identifier NCT02432287). This trial represents a landmark step in translating geroprotector research into human clinical testing.

D-Glucosamine

D-glucosamine is an amino sugar widely used to treat arthritis, though its effectiveness is controversial. Beyond joint health, it promotes lifespan in nematode worms and C57BL/6NRj mice. In humans, current use of glucosamine was associated with a significant 13% decreased risk of death from cancer (hazard ratio 0.87, 95% confidence interval 0.76–0.98) and a 41% reduction in death from respiratory diseases (hazard ratio 0.59, 95% CI 0.41–0.83).

Additional findings include a significant decrease in lung cancer risk and, according to a meta-analysis, glucosamine has the lowest risk of adverse effects compared with other arthritis treatments. The oral supplement may also improve skin aging, reducing the appearance of visible wrinkles and fine lines.

Dihydroergocristine Methanesulfonate

This fungally derived alkaloid salt is a potent vasodilator (a drug that widens blood vessels). It was one of 60 compounds identified in a screen for increased longevity in C. elegans. In human studies of elderly patients with senile dementia of the Alzheimer's type, it was shown to be safe and well tolerated, with rare side effects including mild stomach pain, nausea, and indigestion. Some studies have found statistically significant positive effects on symptoms of age-related cognitive dysfunction.

Ellagic Acid

Ellagic acid is a natural polyphenol found in numerous edible plants, including berries and pomegranates. Its ability to extend C. elegans lifespan is proposed to result from a hormetic effect — meaning a mild stress that triggers protective cellular responses. It has very low acute toxicity: the rat oral LD50 is greater than 20 g/kg, and rat studies showed good tolerability. It also prevents certain age-related changes at the cellular level.

Deprenyl (Selegiline)

Deprenyl protects human neurons from apoptosis (programmed cell death) induced by various insults, likely by interfering with early apoptosis signaling events. It may be applicable to slowing the deterioration of neurons during advancing age.

Clinical Implications: What This Means for Patients

This research framework matters for patients in several direct ways. First, it establishes a standardized way to evaluate claims about anti-aging treatments, helping distinguish promising therapies from hype. Second, many of the top candidate compounds — like metformin, acarbose, and glucosamine — are already approved drugs or widely available supplements, meaning they could move into human clinical trials relatively quickly.

Some encouraging signs are already visible. The mTOR inhibitor RAD001 (everolimus) has been evaluated for its effects on immunosenescence (the age-related decline of the immune system) and showed promising results. Metformin is being tested in healthy adults for its effects on aging itself.

The authors also note that a therapeutic approach targeting aging itself could be uniquely powerful because it works on the common cause of many chronic diseases rather than treating each disease separately. This one-to-many approach could dramatically change how medicine is practiced in the future.

An important example of the framework in action: dasatinib, a senolytic drug that selectively kills senescent cells, shows clear geroprotective potential through its mechanism of action. However, because its effects on lifespan are not yet known, it would be classified as a "potential geroprotector" rather than a confirmed one — a distinction that provides clarity for researchers and regulators.

Limitations: What This Study Couldn't Prove

The authors are transparent about several limitations of their work:

• No single definitive aging biomarker exists. While many candidate biomarkers have been proposed, none can fully substitute for direct lifespan measurement.
• The analysis relied on published literature with minimal judgment on data quality. The authors note that while this approach reduces bias, readers are encouraged to examine the direct literature for specific compounds of interest.
• Increased lifespan in animal models does not guarantee human benefit. Even with all criteria met, translation to the clinic remains uncertain.
• The criteria itself is a proposal, not a validated tool. The system needs to be adopted, tested, and refined by the broader scientific community.
• Some potential geroprotectors may not increase stress resistance — the authors acknowledge this correlation is strong but not universal.

Additionally, the original review is from 2016; the field has advanced since publication, and readers should seek updated information on any specific compound.

Recommendations for Patients

Based on this review, here are practical takeaways for patients:

1. Be skeptical of unproven "anti-aging" products. The fact that a substance extends lifespan in worms or mice does not mean it works in humans. Use the scientific criteria described in this article — evidence of lifespan extension, biomarker improvements, acceptable toxicity, minimal side effects, and quality of life benefits — as a checklist when evaluating claims.
2. Several promising candidates are already approved drugs or supplements. Metformin and acarbose are FDA-approved diabetes medications. Glucosamine is a widely available over-the-counter supplement. However, this does not mean you should self-prescribe them for anti-aging purposes — clinical trials in healthy adults are still ongoing.
3. Focus on what's proven. While researchers work toward pharmaceutical geroprotectors, lifestyle interventions (regular exercise, healthy diet, stress management, adequate sleep) remain the best-documented methods for extending healthspan — the disease-free period of life.
4. Watch for developments from clinical trials. The metformin trial in healthy adults (NCT02432287) and studies of other candidates represent important milestones. As the scientific community adopts standardized criteria, more compounds will likely enter human testing.
5. Remember the goal is healthspan, not just lifespan. An anti-aging treatment that extends years of frailty has little value. Any legitimate geroprotector must also improve or maintain quality of life.

Frequently Asked Questions

What is a geroprotector?

A geroprotector is a substance that slows aging, repairs age-related damage, and extends healthy lifespan. The term was introduced by Ilya Mechnikov in 1910 and means 'protecting against aging.' More than 200 substances are classified as geroprotectors, each reported to slow aging or increase lifespan in organisms ranging from yeast and worms to fruit flies and rodents.

Why haven't anti-aging drugs reached the market yet?

Four major reasons are identified: there is no unified scientific concept of aging, no comprehensive system of human aging biomarkers, aging is not recognized as a disease (so regulators and companies are reluctant to invest), and there is no consensus on criteria for what counts as a geroprotector or how to rate effectiveness. This lack of standardization hampers progress at every stage.

What are the primary criteria for a geroprotector?

The five must-have criteria are: increased lifespan, amelioration of human aging biomarkers, acceptable toxicity, minimal side effects at therapeutic dosage, and improvement in health-related quality of life. These are non-negotiable requirements. For example, there must be several orders of magnitude difference between the lifespan-extending dose and the toxic dose.

What did the metformin trial in healthy adults involve?

Based on evidence that metformin can reduce diabetes-related and all-cause mortality, heart attacks, and any diabetes-related endpoint in individuals with type 2 diabetes, scientists launched a clinical trial to investigate whether metformin can also reduce mortality in healthy adults. The trial identifier is NCT02432287. It represents a landmark step in translating geroprotector research into human clinical testing.

What does 'healthspan' mean and why is it important?

Healthspan is the fully active, disease-free period of life. The authors stress that simply extending lifespan isn't enough; some long-lived mutant worms had poorer quality of life with impaired functional capabilities. The real goal for translation into humans should be an increase in healthspan. An anti-aging treatment that extends years of frailty has little value.

What are the limitations of this evaluation system?

The authors acknowledge several limitations: no single definitive aging biomarker exists; the analysis relied on published literature with minimal judgment on data quality; increased lifespan in animal models does not guarantee human benefit; the criteria itself is a proposal, not a validated tool; and some potential geroprotectors may not increase stress resistance. The original review is from 2016, so readers should seek updated information.

When should someone considering an anti-aging drug like metformin or acarbose seek a second opinion?

A second opinion is worth seeking when a product or supplement is promoted for anti-aging based only on lifespan extension in worms, flies, or mice, since that does not mean it works in humans. It also helps when a candidate such as metformin, acarbose, or glucosamine is suggested for anti-aging use outside an ongoing clinical trial in healthy adults. A reviewer can check the evidence against the five primary criteria: lifespan extension, biomarker improvement, acceptable toxicity, minimal side effects, and quality-of-life benefit. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article Title: criteria for evaluation of geroprotectors

DOI: 10.1111/acel.12463

Authors: Alexey Moskalev, Elizaveta Chernyagina, Vasily Tsvetkov, Alexander Fedintsev, Mikhail Shaposhnikov, Vyacheslav Krut'ko, Alex Zhavoronkov, and Brian K. Kennedy

Journal: Aging Cell (2016), Volume 15, pages 407–415. DOI: 10.1111/acel.12463

Affiliations: Engelhardt Institute of Molecular Biology (Russia), Institute of Biology of Komi Science Center (Russia), Moscow Institute of Physics and Technology, Pirogov Russian National Research Medical University, Institute for Systems Analysis (Russia), D. Rogachev FRCCenter for Pediatric Hematology/Oncology/Immunology, The Biogerontology Research Foundation (UK), and the Buck Institute for Research on Aging (USA).

Note: This patient-friendly article is based on peer-reviewed research published in an open-access format under the Creative Commons Attribution License. It has been adapted to make the scientific content more accessible to general readers. The original article should be consulted for full scientific rigor and complete referencing.