Therapeutics

17α-Estradiol is a stereoisomer of the dominant estrogen 17β-estradiol with much weaker feminizing activity. In the NIA Interventions Testing Program, it consistently extended median lifespan in male mice, possibly via hypothalamic and metabolic effects. Mechanism is incompletely understood and human longevity data do not exist; it is not approved or established as a human anti-aging therapy.

Acarbose is an alpha-glucosidase inhibitor approved for type 2 diabetes mellitus. By blocking intestinal carbohydrate breakdown, it blunts postprandial glucose and insulin spikes and shifts substrate to colonic fermentation. In the NIA Interventions Testing Program, acarbose extended median lifespan in male mice and modestly in females, an effect attributed to glycemic smoothing and microbiome shifts. Off-label longevity use in humans is investigational; gastrointestinal side effects (flatulence, diarrhea) limit tolerability.

Low-dose aspirin (typically 75–100 mg daily) is an irreversible COX-1 inhibitor that suppresses platelet thromboxane A2, reducing platelet aggregation. It is approved for secondary prevention of myocardial infarction and ischemic stroke, where benefit clearly outweighs bleeding risk. The ASPREE trial in healthy older adults showed no cardiovascular benefit, increased major bleeding, and a signal of increased all-cause mortality. Current guidelines discourage routine primary prevention; the USPSTF 2022 recommends individualized decision-making in adults 40–59 with at least 10 percent 10-year CVD risk and recommends against initiation in adults aged 60 or older. Cancer-prevention signals remain investigational.

Berberine is an isoquinoline alkaloid found in multiple plant genera, including Berberis, Hydrastis canadensis (goldenseal), and Coptis chinensis. It is sold as a dietary supplement in most jurisdictions and is not an approved drug in the EU or US. Berberine inhibits mitochondrial complex I, raising the AMP:ATP ratio and thereby activating AMPK downstream; small trials show modest reductions in fasting glucose, HbA1c, LDL cholesterol, and triglycerides in metabolic syndrome and type 2 diabetes. Marketed informally as natural metformin, evidence quality is limited, product purity varies, and CYP3A4-mediated drug interactions warrant caution. Longevity use is investigational.

BPC-157 is a synthetic 15-amino-acid peptide derived from a sequence in human gastric juice, marketed for tendon, ligament, and gut healing. Animal studies suggest pro-angiogenic and tissue-repair effects, but human clinical-trial data are very limited, comprising only a small number of pilot studies with no large well-controlled RCTs. It is not approved by the FDA or EMA, has been added to FDA restriction lists, and is prohibited at all times under WADA category S0 (Unapproved Substances), as it has not been approved by any governmental health authority for human therapeutic use.

D+Q is one of the most studied senolytic combinations: dasatinib (a tyrosine-kinase-inhibitor cancer drug) plus quercetin (a flavonoid), given intermittently and designed to selectively eliminate or reduce senescent-cell burden. Preclinical studies show improvements in physical function and tissue health in aged mice. Human data are limited to small pilot trials in IPF, diabetic kidney disease, and frailty, which have shown reductions in senescence markers; efficacy as an anti-aging therapy remains unproven and use is off-label.

Gene therapy delivers genetic material to add, silence, or edit genes — typically via AAV vectors for stable transgene expression and lipid nanoparticles for transient nucleic-acid delivery (e.g., mRNA, gene-editing components). Longevity targets include telomerase (TERT), follistatin, Klotho, and partial reprogramming via OSK (Oct4, Sox2, Klf4 — three Yamanaka factors, omitting c-Myc to reduce oncogenicity). Rodent data are strong for some constructs, but human applications remain pre-clinical or run as small offshore or patient-paid programs outside FDA-regulated frameworks (BioViva, Libella). Risks include immunogenicity, oncogenicity, and off-target editing; no anti-aging gene therapy is approved.

GLP-1 receptor agonists (e.g. liraglutide, semaglutide, dulaglutide) mimic the incretin hormone glucagon-like peptide-1, stimulating glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and reducing appetite. Approved indications include type 2 diabetes and obesity; large trials show reduced cardiovascular events and, more recently, kidney and heart-failure benefits. Longevity-relevant effects include weight loss, improved glycemia, and possible neuroinflammatory dampening. Off-label use purely for healthspan extension in metabolically healthy adults remains investigational.

Menopausal HRT replaces estrogen, typically combined with a progestogen in women with a uterus, to relieve vasomotor symptoms, protect bone, and treat genitourinary symptoms. Per WHI re-analyses and the timing hypothesis, the benefit-risk profile is more favorable when initiated within roughly ten years of menopause or before age 60. VTE risk is greater with oral estrogen than with transdermal preparations, and breast cancer risk is greater with combined estrogen+progestogen than estrogen-alone, rising with duration. It is symptom- and risk-directed therapy, not a proven life-extension intervention.

Metformin is a biguanide oral antidiabetic drug, first-line therapy for type 2 diabetes mellitus. It lowers hepatic gluconeogenesis and improves insulin sensitivity, partly via mitochondrial complex I inhibition and indirect AMPK activation. Observational data suggest reduced all-cause mortality and cancer incidence in diabetics, motivating the TAME trial in non-diabetic older adults. Off-label longevity use remains investigational; benefit in metabolically healthy people is unproven and may even blunt exercise adaptations.

Peptide therapy uses short amino-acid chains, often injected, intended to modulate growth hormone (e.g., sermorelin, ipamorelin), tissue repair, or metabolism. A few peptides are approved for narrow indications, but most longevity uses are off-label or sourced as research chemicals. Human evidence for anti-aging endpoints is sparse, quality control of compounded products is variable, and regulatory bodies (e.g., FDA) have restricted several popular peptides.

Plasmapheresis is the umbrella term for extracorporeal procedures that separate plasma from cellular blood components; technique varies, with plasma either fractionated or filtered and partially returned, or wholly removed and replaced as in TPE. It is established for autoimmune and hyperviscosity disorders, where its dominant mechanism is removal of pathogenic plasma factors such as antibodies, immune complexes, and inflammatory mediators. In longevity contexts it is proposed to dilute pro-aging plasma factors, but evidence for healthy-aging benefit is preliminary.

Rapamycin (sirolimus) is a macrolide mTORC1 inhibitor approved as an immunosuppressant to prevent kidney transplant rejection and to treat lymphangioleiomyomatosis. By inhibiting mTORC1, it slows protein synthesis, enhances autophagy, and extends lifespan in yeast, worms, flies, and mice across multiple labs. Off-label use for human longevity remains investigational; clinical trials are evaluating intermittent low-dose protocols, but efficacy and long-term safety in healthy adults are unproven.

Semaglutide is a long-acting GLP-1 receptor agonist approved for type 2 diabetes (Ozempic, Rybelsus) and chronic weight management (Wegovy). The SELECT trial demonstrated a 20 percent reduction in major adverse cardiovascular events in adults with obesity and established cardiovascular disease without diabetes. Longevity-relevant mechanisms include sustained weight loss, improved insulin sensitivity, lower inflammation, and possible cognitive and renal protection. Off-label use solely for lifespan extension in healthy adults is investigational and not endorsed.

Senolytic therapy uses drugs or natural compounds to selectively eliminate senescent cells, which accumulate with age and secrete a multi-component secretome (the SASP) of inflammatory cytokines and chemokines, growth factors, and tissue-remodeling proteases such as MMPs. By targeting senescent-cell anti-apoptotic pathways (SCAPs) and promoting selective apoptosis in these cells, senolytics aim to reduce age-related dysfunction. Evidence is robust in animal models, but human trials remain small and early; clinical efficacy, optimal dosing, and long-term safety are unproven.

SGLT2 inhibitors (gliflozins, e.g. empagliflozin, dapagliflozin) block renal sodium-glucose cotransporter 2, causing urinary glucose excretion. They are approved for type 2 diabetes, heart failure (preserved and reduced ejection fraction), and chronic kidney disease, with robust cardiovascular and renal mortality benefits. Proposed mechanisms include a hypothesized ketone-mediated cardiac fuel shift, mild caloric loss, and reduced glomerular hyperfiltration, though the dominant pathway remains debated. Canagliflozin extended lifespan in male mice. Off-label longevity use in non-indicated adults remains investigational.

Statins (HMG-CoA reductase inhibitors, e.g. atorvastatin, rosuvastatin) lower hepatic cholesterol synthesis and upregulate LDL receptors, reducing circulating LDL cholesterol. They are approved for primary and secondary prevention of atherosclerotic cardiovascular disease, with strong randomized evidence for reduced cardiovascular mortality. Longevity-relevant pleiotropic effects include endothelial improvement, anti-inflammatory action, and possible plaque stabilization. In low-risk individuals, the absolute mortality benefit is small and less certain; benefit is most clearly demonstrated in higher-risk and secondary prevention populations. Off-label use purely for longevity is investigational.

TRT restores testosterone in men with documented hypogonadism (low serum testosterone plus symptoms), via gels, injections, or pellets. Benefits include improved libido, mood, lean mass, and bone density. Risks include erythrocytosis, fertility suppression, and possible cardiovascular effects; the recent TRAVERSE trial suggested cardiovascular non-inferiority but not benefit. TRT is not validated as a longevity therapy in eugonadal men and remains controversial outside clinical hypogonadism.

TPE is a specific form of plasmapheresis in which approximately one to one-and-a-half plasma volumes are removed and replaced per session with albumin, saline, or donor plasma, rather than re-infused. It is standard of care for several neurologic and hematologic diseases. Longevity interest stems from rodent dilution studies suggesting rejuvenation; small human trials (e.g., in Alzheimer's) are early and ongoing, with no proven anti-aging benefit.

Tirzepatide is a once-weekly dual GIP and GLP-1 receptor agonist approved for type 2 diabetes (Mounjaro) and chronic weight management (Zepbound). The dual incretin action produces greater weight loss and HbA1c reduction than selective GLP-1 agonists in head-to-head trials, with cardiovascular and sleep apnea benefits emerging. Longevity-relevant effects parallel GLP-1 agonists: improved metabolism, weight reduction, and reduced cardiometabolic risk. Off-label use in metabolically healthy adults for lifespan extension remains investigational.