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.

Adeno-associated virus (AAV) gene therapy uses recombinant AAV capsids to deliver a transgene cassette — typically a promoter, coding sequence, and poly-A signal — to target tissues. Different serotypes (AAV9 for CNS/muscle, AAV8 for liver, AAV2 for retina) have distinct tissue tropisms determined by capsid-surface receptor interactions, and the ~4.7 kb packaging limit constrains which genes can be delivered as a single construct. Pre-existing NAb titres and T-cell responses to capsid proteins are the principal immunogenicity barriers, and in some trials have required plasmapheresis or high-dose immunosuppression to avoid clearance or hepatotoxicity. In longevity-relevant preclinical work, AAV vectors have been used to deliver Klotho, TERT, follistatin, and FGF21 transgenes in rodents, yielding functional improvements; no anti-aging AAV product has received regulatory approval, and all human longevity applications remain investigational or compassionate-use.

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 an early signal of increased all-cause mortality (largely cancer-driven and attenuated in ASPREE-XT extended follow-up). 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.

Bisphosphonates are synthetic analogues of pyrophosphate that bind avidly to hydroxyapatite in bone mineral and are taken up by osteoclasts during bone resorption, where nitrogen-containing bisphosphonates (alendronate, zoledronate, risedronate) inhibit farnesyl diphosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and survival. They are approved for osteoporosis, Paget's disease, hypercalcaemia of malignancy, and bone metastases, where they significantly reduce fracture risk and skeletal-related events. Observational and secondary-analysis data suggest broader aging-relevant effects: zoledronate (intravenous, annual) was associated with reduced all-cause mortality in a randomised trial in patients with recent hip fracture (HORIZON Recurrent Fracture Trial; Lyles et al., 2007, NEJM) and in observational cohorts, and bisphosphonate use has been associated with reduced breast, colorectal, and possibly other cancers in several epidemiological studies, though residual confounding cannot be excluded. Geroscience interest centres on possible senolytic-adjacent effects — bisphosphonates deplete osteoclast progenitors and may selectively reduce calcification-associated senescent cell burden — but these mechanisms are hypothetical in humans. Side effects include oesophageal irritation, osteonecrosis of the jaw (rare, mainly with high-dose intravenous use), and atypical femoral fractures with prolonged therapy.

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.

Denosumab is a fully human IgG2 monoclonal antibody that binds and neutralizes RANKL (receptor activator of nuclear factor-κB ligand), the cytokine required for osteoclast differentiation, activation, and survival; by blocking the RANK–RANKL axis it profoundly suppresses bone resorption. It is FDA-approved for osteoporosis in postmenopausal women and men at high fracture risk (Prolia, 60 mg SC every 6 months), prevention of skeletal-related events in bone metastases (Xgeva, higher dose), and giant cell tumour of bone. Unlike bisphosphonates, RANKL inhibition also affects immune cells and tumour microenvironments because RANKL is expressed on osteoblasts, activated T cells, and stromal cells beyond bone; this has prompted research into oncological and immunological applications. Observational data suggest possible cardiovascular and all-cause mortality reductions in denosumab-treated osteoporosis patients beyond fracture prevention, paralleling findings with bisphosphonates, but confounding and frailty-bias complicate interpretation. A critical safety feature is rebound bone loss if therapy is discontinued without transitioning to a bisphosphonate, as osteoclast activity surges; rare osteonecrosis of the jaw and atypical femoral fractures are also reported.

Exosomes are extracellular vesicles of 30–150 nm diameter that originate from the endosomal multivesicular body pathway and carry a cargo of proteins, lipids, mRNAs, miRNAs, and other non-coding RNAs that can modulate gene expression and cell behaviour in recipient cells. In aging research, exosomes derived from young plasma or from mesenchymal stem cells (MSC-EVs) have shown rejuvenating effects in rodent models — improving cardiac function, cognitive performance, and tissue regeneration — and are proposed as a cell-free alternative to plasma transfusion or stem cell therapy with potentially lower immunogenic risk. Regulatory classification is contested: the FDA considers most exosome products as biologics subject to IND application for clinical use, and in 2019 issued a safety alert warning that exosome products marketed for anti-aging, orthopedic, or hair loss indications outside clinical trials have not demonstrated safety or efficacy. The clinical evidence base consists primarily of small pilot studies and case series; controlled randomised trial data in aging are absent. Standardisation of isolation method, cargo characterisation, potency assays, and dosing remains an unresolved challenge across the field, and exosome products sold directly at clinics should be viewed with significant caution.

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 (the three Yamanaka factors Oct4, Sox2 and Klf4 — 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 demonstrate reduced cardiovascular events, now-approved kidney-disease risk reduction in type 2 diabetes with chronic kidney disease (semaglutide, FDA January 2025, FLOW trial), and investigational heart-failure symptom improvements in HFpEF. 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.

Heterochronic parabiosis (HCP) is an experimental surgical technique in which the circulatory systems of a young and an old animal are joined by anastomosis of subcutaneous vasculature, exposing each partner continuously to the other's blood. Classic studies by Clive McCay in the 1950s and a revival by Irina and Michael Conboy (2005, Nature), Amy Wagers, Saul Villeda, and colleagues in the 2000s–2010s showed that old mice conjoined with young partners exhibit improvements in muscle regeneration, neurogenesis, cardiac hypertrophy, and liver function, while young mice show partial deterioration. Two competing mechanistic hypotheses emerged: the young-factors model, proposing that circulating rejuvenating factors in young blood are responsible — highlighted by controversy over GDF11, which was initially championed and then disputed as a beneficial rejuvenation factor — and the dilution model, proposed by Irina Conboy and colleagues, arguing that dilution of pro-aging factors (TGF-β, β2-microglobulin) accumulated in old blood is the dominant mechanism, a view supported by experiments using young saline-albumin exchange rather than young blood specifically. Human translation efforts include Alkahest (spin-out from Villeda's group), which has fractionated plasma into defined protein fractions (GRF6019) for Alzheimer's and Parkinson's trials, and small commercial young-plasma infusion services that preceded regulatory scrutiny; the FDA issued a safety alert in 2019 warning against unproven commercial young-plasma infusions. No plasma-based therapy for aging is currently approved by the FDA or EMA.

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.

Klotho is a transmembrane protein and co-receptor for FGF23 that declines markedly with age; its soluble circulating form (s-Klotho) suppresses Wnt and TGF-β signalling and has been associated with renal function, cognitive health, and cardiovascular protection in observational studies. In mouse models, transgenic Klotho overexpression has extended lifespan (Kurosu et al., 2005), and AAV-mediated Klotho gene therapy has improved kidney function and rescued cognitive deficits in disease models. In aged rhesus macaques, peripheral injection of recombinant Klotho protein — not gene therapy — enhanced cognition (Castner et al., 2023); AAV-Klotho gene therapy in primates has not yet been published. Human longevity application remains strictly preclinical; BioViva and affiliated researchers have reported self-administered gene therapy experiments in single individuals outside regulated clinical frameworks, but these lack controlled safety or efficacy data and should not be interpreted as evidence of benefit. Risks include disruption of FGF23-phosphate homeostasis, possible ectopic calcification, and the general immunogenicity and off-target concerns of systemic AAV delivery.

Mesenchymal stem cells (MSCs) are multipotent stromal progenitors capable of differentiating into osteoblasts, chondrocytes, and adipocytes, and are isolated from bone marrow, adipose tissue, umbilical cord (Wharton's jelly), placenta, and dental pulp, with umbilical cord-derived MSCs increasingly favoured for allogeneic use due to lower immunogenicity and higher proliferative capacity. Despite early assumptions of direct tissue engraftment and replacement, current evidence indicates that transplanted MSCs rarely engraft stably at target tissues; instead, the dominant mechanism of action is paracrine, mediated by secreted cytokines, growth factors, extracellular vesicles (exosomes and microvesicles), and mitochondrial transfer, which modulate local immune responses, reduce fibrosis, support angiogenesis, and dampen senescent cell secretome activity. In age-related and chronic disease contexts, MSC therapies have been investigated in clinical trials for osteoarthritis, graft-versus-host disease, Crohn's disease, heart failure, COPD, and frailty, with graft-versus-host disease being the setting with the most established regulatory acceptance in some jurisdictions. For aging and longevity applications specifically, small trials have reported functional improvements in frailty endpoints, but sample sizes, follow-up durations, and outcome standardization remain insufficient for definitive conclusions. Regulatory status varies by region: the EMA and FDA require approval as advanced-therapy medicinal products (ATMPs) or biologics, and many administered products operate outside approved frameworks. Long-term safety data, including oncogenicity risk from repeated dosing, are not fully established.

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 still-largely-unfunded TAME trial proposal (delayed since 2016, partial ARPA-H involvement announced 2024 but enrollment not yet confirmed). Off-label longevity use remains investigational; benefit in metabolically healthy people is unproven and may even blunt exercise adaptations.

Methylene blue (MB) is a synthetic phenothiazine dye with FDA approval (Provayblue, 2016) for treatment of acquired methemoglobinemia at an initial dose of 1 mg/kg intravenously, with a repeat dose of 1 mg/kg if needed (total up to 2 mg/kg). At low concentrations (nanomolar to low micromolar), it acts as a redox cycler in the mitochondrial electron transport chain, accepting electrons from NADH and donating them to cytochrome c, thereby bypassing dysfunctional complexes I and III and supporting ATP synthesis. In cell culture and rodent models, low-dose MB has reduced mitochondrial reactive oxygen species, improved memory in aged animals, and attenuated neurodegeneration-related pathology. Interest in MB for aging stems partly from a small number of human trials investigating cognitive effects in healthy older adults or early Alzheimer's disease, with mixed and modest results; no aging or longevity indication has been approved, regulatory frameworks for low-dose oral use vary by country, and recommendations for off-label use as a longevity agent are unsupported by RCT evidence.

Mitochondrial transplantation involves the direct transfer of intact, metabolically functional mitochondria — isolated from autologous or allogeneic tissue — into ischaemic or otherwise bioenergetically compromised cells or organs to supplement or replace dysfunctional mitochondria. The best-documented clinical context is paediatric cardiac surgery: McCully and colleagues (Boston Children's Hospital) reported in a preliminary 2017 JTCVS communication that autologous mitochondria injected into ischaemia-injured myocardium improved ventricular function in children with postcardiotomy ECMO-dependent cardiogenic shock; a larger 2020 JTCVS case series (n=24) showed 80% successful ECMO separation versus 29% in controls. This application is now in early clinical study (NCT02851758). Mechanistic proposals include import via clathrin-mediated endocytosis, macropinocytosis, and direct membrane fusion, though the dominant uptake pathway and long-term mitochondrial survival in recipient cells remain under investigation. Application to aging is hypothetical: in preclinical models, intravenous mitochondrial infusion has been reported to improve muscle function and cognitive markers in aged rodents, but the route, source tissue, dosing, and safety profile for systemic aging applications are not established, and no approved indication for aging exists.

Nicotinamide (NAM, also called niacinamide) is the amide form of vitamin B3 and a direct precursor in NAD+ biosynthesis via the salvage pathway enzyme NAMPT. It is biochemically distinct from the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR): whereas NR and NMN feed into the salvage pathway before NAM's NAMPT entry point, NAM is the common end-product of NAD+ consumption by sirtuins, PARPs, and CD38, making intracellular NAM accumulation a feedback inhibitor of SIRT1 and other sirtuins at high concentrations. This dual role — both precursor and sirtuin inhibitor — complicates interpretation of supplementation studies and distinguishes it mechanistically from NR/NMN. NAM has established medical uses: topical niacinamide is widely used for acne and skin barrier function, and oral high-dose nicotinamide (500 mg twice daily) reduced actinic keratoses and non-melanoma skin cancer rates in a randomized trial (Chen et al., 2015, NEJM). Its use as a systemic longevity supplement is investigational and the net effect on sirtuin-dependent processes at supplemented doses in humans is not established.

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.

Pioglitazone is a thiazolidinedione PPARγ agonist approved for type 2 diabetes mellitus as an insulin sensitizer, acting primarily by promoting the differentiation and lipid uptake of adipocytes, thereby reducing ectopic fat deposition and improving systemic insulin sensitivity. PPARγ activation also modulates inflammatory gene expression and macrophage polarization towards anti-inflammatory phenotypes, which has generated interest in pioglitazone for age-related conditions beyond glycaemic control. The IRIS trial (Kernan et al., 2016, NEJM) demonstrated reduced cardiovascular events in non-diabetic patients with insulin resistance and prior stroke or TIA, providing evidence for cardiovascular benefit in a metabolically compromised but non-diabetic population. Nir Barzilai and colleagues have included pioglitazone in geroscience cohort discussions as a candidate that addresses metabolic and inflammatory hallmarks of aging. Long-term safety concerns include risk of congestive heart failure, bone loss, and a possible association with bladder cancer; France and Germany suspended use in 2011 following safety signals, and the EMA did not withdraw authorisation EU-wide but added contraindications (active or past bladder cancer, uninvestigated haematuria) and strict labelling restrictions, limiting its investigational use as a longevity agent.

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. The PEARL trial (Moel et al., Aging-US April 2025) reported safety similar across groups; the primary efficacy endpoint of visceral adipose tissue change was not met, but secondary outcomes showed dose-dependent improvements in lean mass and pain in women on 10 mg/week.

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.

A senescent-cell vaccine is an immunological strategy aimed at training the adaptive immune system to recognize and eliminate senescent cells in vivo, analogous to anti-tumour vaccination. The approach was demonstrated preclinically by Suda and colleagues (2021, Nature Aging): mice vaccinated with peptides derived from glycoprotein nonmetastatic melanoma protein B (GPNMB), a surface antigen overexpressed on senescent cells, developed GPNMB-specific cytotoxic T-lymphocyte responses that reduced senescent cell burden, improved physical function, and partially replicated healthspan benefits seen with pharmacological senolytics in progeroid (Ercc1-mutant accelerated-aging) and diet-induced obese mouse models. The concept is in early discovery phase: GPNMB is not exclusively expressed on senescent cells, potential immune tolerance and autoimmunity risks have not been evaluated in humans, no clinical trial has been initiated, and whether a single antigen target can cover the heterogeneous senescent cell landscape across tissues remains unresolved. This is a preclinical proof-of-concept, not an available or approaching clinical product.

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.

Sermorelin is a synthetic 29-amino-acid analogue of endogenous growth hormone-releasing hormone (GHRH 1–29) that stimulates pituitary somatotrophs to secrete growth hormone (GH) in a pulsatile, feedback-sensitive manner, in contrast to exogenous GH administration which suppresses endogenous production. It was formerly FDA-approved for paediatric GH deficiency (Geref; the manufacturer notified FDA of discontinuation in 2008, and FDA formally withdrew approval effective June 2009, for commercial rather than safety reasons) and remains approved in some other jurisdictions. In anti-aging medicine, sermorelin is widely prescribed off-label at clinics to raise GH/IGF-1 axis activity, reduce body fat, and improve lean mass and sleep quality in middle-aged and older adults; however, controlled evidence for meaningful longevity or functional outcomes is limited, and the GH secretagogue class broadly lacks Phase III efficacy data for aging indications. Adverse effects include injection-site reactions, fluid retention, and theoretical concern about promotion of occult neoplasia given GH/IGF-1 mitogenic signalling; its use is not endorsed by major endocrinological societies for anti-aging purposes.

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.

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase; its somatic expression is repressed in most adult human tissues, leading to progressive telomere shortening with each cell division. AAV-delivered TERT transgenes have extended median lifespan, delayed frailty, and improved metabolic and neuromuscular phenotypes in middle-aged and old mice in work from the Blasco laboratory, with a single administration showing lasting effects without elevated cancer incidence in the mouse models studied. Human longevity application remains preclinical; the concern that telomerase activation could promote tumour growth by enabling unlimited replicative capacity in cells harbouring oncogenic mutations is a central safety caveat that has not been resolved in human data. Self-administered TERT gene therapy by individuals outside regulated trials (reported in the context of BioViva/Andrews) lacks peer-reviewed safety or efficacy evaluation and represents an extreme scientific and safety risk.

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 cardiovascular effects; the recent TRAVERSE trial suggested cardiovascular non-inferiority but not benefit, though TRAVERSE also found increased rates of atrial fibrillation and venous thromboembolism in the testosterone arm. 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.

Thymosin α-1 (Tα1) is a 28-amino-acid peptide derived from prothymosin α, naturally produced by thymic epithelial cells, that modulates innate and adaptive immunity by activating TLR signalling in dendritic cells and monocytes and promoting Th1-type T-cell responses. The thymus undergoes substantial involution from early adulthood, and declining thymic output with age contributes to T-cell senescence and immune ageing; Tα1 supplementation is proposed to partially compensate for this deficit. Thymalfasin (Zadaxin, SciClone Pharmaceuticals) is approved in over 35 countries — but not the United States — as an adjunct therapy for chronic hepatitis B and C and as an immunostimulant in patients with impaired immunity; it has been used off-label during COVID-19 outbreaks in several countries. Human evidence for anti-aging or longevity benefit is absent; trials in cancer and infection support immunomodulatory activity, but effect sizes and consistency vary. Tα1 is widely marketed by anti-aging clinics; its regulatory classification ranges from approved drug to unregulated peptide depending on jurisdiction. FDA added thymosin α-1 to Category 2 of the interim 503A bulks list on 29 September 2023; the substance was removed from Category 2 effective 27 September 2024 after the nominator withdrew its nomination, and on 4 December 2024 the FDA Pharmacy Compounding Advisory Committee (PCAC) voted against its inclusion on the 503A allowed bulks list, leaving it not eligible for use in 503A compounding in the US.

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; the FDA approved Zepbound for moderate-to-severe obstructive sleep apnea in adults with obesity in December 2024, while cardiovascular outcome benefits remain under investigation. 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.

Urolithin A is a gut-derived metabolite produced when colonic bacteria transform ellagitannins and ellagic acid — polyphenols found in pomegranates, walnuts, and berries — via species such as Gordonibacter urolithinfaciens; because the requisite microbiome varies between individuals, dietary ellagitannin intake does not reliably raise urolithin A levels in all people. The compound activates mitophagy through mechanisms including inhibition of prohibitin-2 and indirect PINK1/Parkin pathway engagement, and improves mitochondrial respiration in preclinical models. In human randomized trials, a phase I safety and biomarker study (Andreux et al., 2019) established tolerability in older adults, while the ATLAS trial (Singh et al., 2022) in overweight middle-aged adults showed improvements in skeletal muscle mitophagy markers, aerobic endurance, and muscle strength as secondary endpoints; the primary endpoint (peak power output) was not met, and both trials were conducted by Amazentis, the commercial developer. Regulatory status: sold as a dietary supplement in many countries; not approved as a drug; longer-term safety and efficacy trials are ongoing.

Alpha-ketoglutarate (AKG) is a key intermediate of the tricarboxylic acid (TCA) cycle that also serves as an obligate co-substrate for a large family of dioxygenases — including TET methylcytosine hydroxylases and Jumonji-domain histone demethylases — that regulate the epigenome. Plasma AKG levels decline substantially with age in humans, which has motivated its supplementation in longevity research. In a 2020 mouse study (Asadi Shahmirzadi et al., Cell Metabolism), the calcium salt form (CaAKG) significantly extended median lifespan in female mice (by approximately 17%, with ~20% extension at the 90th percentile) while males showed only a non-significant numerical trend (~10%); frailty was reduced in both sexes, though the trial was conducted in a single cohort rather than through the rigorous multi-site NIA Interventions Testing Program. A small 7-month open-label observational analysis of 42 self-selected users of the commercial formulation Rejuvant (Katcher et al., 2021) reported reductions in biological age as estimated by the TruAge DNA-methylation clock, but the study was industry-funded, single-arm without randomisation, and lacked a pre-registered primary endpoint. CaAKG is marketed as a supplement; no drug approval exists for aging indications, and independent replication in humans is absent.