Aspirin

Aspirin (acetylsalicylic acid) originates from salicin, a compound isolated from willow bark used medicinally in antiquity and described in the Ebers Papyrus approximately 3,500 years ago. Felix Hoffmann at Bayer first synthesised the acetylated form in 1897, and aspirin entered commercial production in 1899 as an analgesic, antipyretic, and anti-inflammatory agent, becoming one of the highest-volume pharmaceuticals in history before its molecular mechanism was characterised. John Vane identified prostaglandin biosynthesis inhibition as aspirin primary mechanism in 1971, work that earned him the Nobel Prize in Physiology or Medicine in 1982 alongside Bergstrom and Samuelsson. The FDA has approved aspirin for pain, fever, inflammation, and as an antiplatelet agent for cardiovascular prevention in patients with prior myocardial infarction, unstable angina, ischemic stroke, or transient ischemic attack; it is available over the counter in the United States at all doses. Approximately 40,000 metric tons of aspirin are produced globally per year, and it remains the most widely used analgesic-antipyretic in the world despite the availability of acetaminophen and selective COX-2 inhibitors.

Aspirin primary mechanism is irreversible acetylation of the cyclooxygenase enzymes COX-1 and COX-2 at specific serine residues in the active site channel: Ser530 of COX-1 and Ser516 of COX-2. The aspirin acetyl group is covalently transferred to the serine hydroxyl, blocking the arachidonic acid binding channel by steric interference and preventing the cyclooxygenation step that converts arachidonic acid to prostaglandin G2, the committed step in all prostaglandin and thromboxane biosynthesis. In platelets, this irreversible COX-1 inhibition permanently eliminates thromboxane A2 synthesis for the 7-to-10-day platelet lifespan, since platelets are anucleate and cannot regenerate COX-1 protein; this mechanism makes once-daily low-dose aspirin sufficient for continuous antiplatelet coverage. Thromboxane A2 is a potent platelet activator and vasoconstrictor; its elimination shifts the local eicosanoid balance toward prostacyclin (PGI2), which is vasodilatory and inhibitory of platelet aggregation. In nucleated cells, COX-2 is regenerated within 4 to 6 hours, meaning anti-inflammatory and analgesic effects require repeated dosing throughout the day. At plasma salicylate concentrations achieved with anti-inflammatory doses (3 to 4 g per day), two additional mechanisms operate: direct IKKbeta inhibition blocks NF-kappaB nuclear translocation and reduces transcription of TNF-alpha, IL-1beta, and COX-2; and salicylate binding to the AMPK beta1 subunit activates the AMPK energy-sensing kinase independently of COX, as described by Hawley et al. in Science (2012). The selectivity ratio of aspirin for COX-1 over COX-2 of approximately 10:1 to 50:1 is the mechanistic basis for the separation between antiplatelet effects at low doses and anti-inflammatory effects at high doses.

The landscape of aspirin prescribing was fundamentally restructured by the 2018 publication of three landmark primary prevention trials. ASPREE (n=19,114 adults aged 70 or older, median follow-up 4.7 years) found that aspirin 100 mg daily failed to improve disability-free survival (HR 0.89, p=0.10) while increasing all-cause mortality (HR 1.14, 95 percent CI 1.01 to 1.29) and major hemorrhage (HR 1.38, 95 percent CI 1.18 to 1.62), with excess cancer deaths emerging in the aspirin group in the first three years as a particularly unexpected and counterintuitive finding. ARRIVE (n=12,546 moderate-risk adults) found no significant MACE reduction (HR 0.96, p=0.60) with doubled GI bleeding (HR 2.11). ASCEND (n=15,480 diabetics) found a modest 12 percent vascular event reduction (RR 0.88, p=0.01) counterbalanced by a 29 percent increase in major bleeding (RR 1.29, p=0.003), producing near-neutral net clinical benefit. These three trials collectively enrolled over 47,000 participants and established that aspirin for primary prevention is an individualised risk-benefit decision requiring careful assessment rather than a population-level standard of care. The 2019 ACC/AHA primary prevention guidelines responded by recommending against initiating aspirin in adults over 70 and limiting primary prevention use to high-risk adults aged 40 to 70 after careful assessment; the USPSTF issued similar guidance in 2022.

Aspirin is absorbed with oral bioavailability of approximately 68 percent for plain tablets; enteric-coated formulations delay absorption to Tmax of 3 to 4 hours and are not appropriate for loading doses in acute cardiovascular events. Aspirin plasma half-life of 15 to 20 minutes is pharmacodynamically irrelevant for antiplatelet purposes; the effective duration of action is determined by the 7-to-10-day platelet lifespan. Salicylate undergoes dose-dependent Michaelis-Menten elimination, with half-life rising from 2 to 3 hours at antiplatelet doses to 15 to 30 hours at anti-inflammatory doses, explaining why supratherapeutic dose escalation produces disproportionate toxicity and why forced urinary alkalinisation is the cornerstone of salicylate poisoning management. The critical drug-drug interaction concern in cardiovascular patients is ibuprofen and non-selective NSAIDs: these drugs compete with aspirin for the COX-1 Ser530 acetylation site, and if taken before aspirin, block irreversible acetylation and abolish the antiplatelet effect for the duration of the reversible NSAID binding; acetaminophen is the recommended analgesic for patients on antiplatelet aspirin. From a longevity and off-label perspective, the salicylate-AMPK mechanism raises the hypothesis that aspirin metabolic and anti-cancer effects extend beyond COX inhibition; however, the ASPREE signal of increased cancer deaths in elderly users in the first three years of use underscores that net effect depends critically on patient age, baseline cancer risk, and duration of use, and aspirin is not recommended as a longevity intervention outside specific high-risk groups.

Mechanism of Action

Irreversible COX Acetylation and Platelet Biology

Aspirin transfers its acetyl group from the ester bond to the hydroxyl group of a specific serine residue in the active site channel of cyclooxygenase enzymes: Ser530 of COX-1 and Ser516 of COX-2. This covalent acetylation sterically blocks the hydrophobic arachidonic acid binding channel, preventing arachidonic acid from reaching the catalytic Tyr385 residue where the cyclooxygenation reaction occurs. The result is permanent suppression of prostaglandin G2 formation, the committed and rate-limiting step in all prostaglandin, prostacyclin, and thromboxane A2 biosynthesis.

The antiplatelet effect of aspirin is uniquely powerful because platelets are anucleate cells incapable of synthesising new proteins. Once a platelet COX-1 molecule is irreversibly acetylated, that platelet can never produce thromboxane A2 again. A single oral dose of 81 mg aspirin achieves near-complete (greater than 95 percent) inhibition of platelet TXA2 synthesis within 1 hour, and this inhibition persists for the entire 7-to-10-day platelet lifespan. Because only approximately 10 percent of the platelet pool is replaced daily by newly released platelets from megakaryocytes, once-daily dosing maintains near-complete platelet COX-1 suppression indefinitely at steady state.

Thromboxane A2 is a potent platelet activator that binds TP receptors on adjacent platelets, amplifying the aggregation response, and a vasoconstrictor that promotes local vessel spasm at sites of vascular injury. By eliminating TXA2 synthesis, aspirin shifts the eicosanoid balance toward prostacyclin (PGI2), produced by vascular endothelial cells via COX-2, which is vasodilatory and strongly inhibitory of platelet aggregation through cAMP elevation. This TXA2/PGI2 balance shift is the central mechanism for aspirin cardiovascular protection.

The dose-selectivity relationship deserves emphasis. At low doses (75 to 100 mg daily), aspirin achieves irreversible COX-1 acetylation predominantly in the portal circulation before reaching systemic concentrations, targeting platelets and intestinal cells while sparing most vascular endothelial COX-2 activity. At higher doses, vascular and tissue COX-2 is also acetylated. In nucleated cells (endothelium, macrophages, epithelium), COX-2 regenerates over 4 to 6 hours, requiring sustained or repeated dosing for continuous anti-inflammatory and analgesic effects. The selectivity ratio of aspirin for COX-1 over COX-2, approximately 10:1 to 50:1 depending on assay conditions, is the pharmacological basis for separating antiplatelet dosing from anti-inflammatory dosing.

Prostaglandin E2 Suppression and Cancer Chemoprevention

COX-2 is overexpressed in more than 80 percent of colorectal adenomas and carcinomas and in multiple other solid tumours, driven by oncogenic signaling including RAS, Wnt/beta-catenin, NF-kappaB, and inflammatory cytokines. The prostaglandin E2 produced by overexpressed COX-2 then acts through EP2 and EP4 G-protein-coupled receptors on epithelial cells, immune cells, and tumour stroma to execute a broad pro-tumorigenic programme: EP2/EP4-coupled Gs activation raises cAMP and activates PKA, suppressing apoptosis; EP2/EP4 coupling to PI3K/Akt further promotes cell survival; beta-catenin stabilisation via Akt-mediated GSK-3beta inhibition amplifies Wnt signaling; VEGF upregulation through HIF-1alpha promotes tumour angiogenesis; and expansion of regulatory T-cells and myeloid-derived suppressor cells suppresses antitumour immune surveillance.

Aspirin blocks PGE2 production through irreversible COX-2 acetylation in colonocytes and tumour stroma, depriving early neoplastic cells of this multi-pronged survival and immune-evasion signal. The cancer prevention effect requires sustained duration of use (at least 5 years in most epidemiological data) because aspirin appears to prevent early oncogenic events, such as the expansion of pre-neoplastic clones with APC mutations, rather than suppressing established tumours. The persistence of cancer prevention benefit for 10 or more years after aspirin is stopped, observed in both CAPP2 and population cohorts, is consistent with the hypothesis that aspirin prevents the formation of neoplastic founder clones rather than continuously suppressing tumour growth.

In Lynch syndrome, MMR-deficient cells accumulate frameshift mutations at a high rate and become progressively more dependent on PGE2 for survival signaling, creating a specific vulnerability to aspirin-mediated PGE2 suppression. The CAPP2 trial result, which showed benefits emerging after aspirin cessation rather than during treatment, is consistent with immune-mediated clearance of early neoplastic MMR-deficient clones that were sensitised to immunosurveillance by aspirin prostaglandin suppression.

Salicylate as Direct AMPK Activator

Aspirin is rapidly hydrolysed to salicylate by esterases in the gut wall, portal blood, and liver. Salicylate, historically considered a pharmacologically inert aspirin metabolite, was demonstrated in 2012 by Hawley et al. (Science 2012) to directly activate AMPK through a mechanism distinct from all previously characterised AMPK activators.

Salicylate binds to the beta1 regulatory subunit of the AMPK complex at a specific allosteric site that is physically separate from the AMP/ATP-sensing gamma subunit. This beta1 subunit binding increases AMPK activity directly and also sensitises the complex to activation by the upstream kinase LKB1 (STK11), which phosphorylates the AMPK alpha subunit at Thr172. The requirement for STK11/LKB1 in salicylate-mediated AMPK activation means that cell types or cancer cells lacking functional STK11 show attenuated responses to salicylate, providing a molecular explanation for why aspirin cancer prevention effects may be stronger in STK11-intact epithelia.

Importantly, this AMPK activation occurs at plasma salicylate concentrations achievable with standard therapeutic aspirin doses of 81 to 325 mg daily, meaning this mechanism operates alongside the COX inhibitory mechanism at the doses used for cardiovascular prevention. AMPK activation by salicylate reduces hepatic ACC activity and de novo lipogenesis, suppresses glucose production through FOXO1 pathway inhibition, reduces NF-kappaB-driven inflammatory gene expression through AMPK-mediated IKKbeta regulation, and activates autophagy through mTORC1 suppression. These downstream effects of salicylate-AMPK activation may contribute to aspirin anti-inflammatory and anti-cancer activity through a COX-independent pathway and provide a molecular connection to the metabolic and longevity-associated signaling pathway activated by metformin and exercise.

NF-kappaB Pathway Inhibition

At plasma salicylate concentrations achieved during high-dose anti-inflammatory therapy (3 to 4 g per day), aspirin and salicylate directly inhibit IKKbeta (IkappaB kinase beta), the serine kinase that phosphorylates IkappaB-alpha and triggers its ubiquitination and proteasomal degradation. IKKbeta inhibition prevents IkappaB-alpha phosphorylation, trapping NF-kappaB in the cytoplasm as an inactive IkappaB-bound complex and preventing nuclear translocation and transcriptional activation of inflammatory target genes including TNF-alpha, IL-1beta, IL-6, COX-2, ICAM-1, MMP-9, and Bcl-xL.

This NF-kappaB inhibition mechanism is independent of COX inhibition and explains anti-inflammatory and potentially antiproliferative effects of high-dose aspirin and salicylate that occur in COX-2-null cells. The NF-kappaB pathway is constitutively active in many tumour types and inflammatory diseases; aspirin blockade of this pathway at anti-inflammatory doses provides a secondary anti-cancer mechanism beyond the COX-2/PGE2 axis. At standard antiplatelet doses (81 mg), plasma salicylate concentrations are well below the IKKbeta-inhibitory threshold and this mechanism does not contribute meaningfully to the clinical effect.

Epigenetic Modulation

Evidence for aspirin epigenetic effects has emerged from colorectal cancer research, though the mechanistic characterisation is less advanced than for berberine or metformin. Studies in colorectal cancer cell lines and human colon tissue demonstrate that regular aspirin use is associated with increased methylation at specific CpG sites in the promoters of oncogenes including MLH1 (when silenced by hypermethylation in sporadic CRC), WNT3, and ERBB2, and with reduced methylation of certain tumour suppressor gene promoters.

Aspirin as an acetyl group donor has the theoretical capacity to non-enzymatically acetylate histones and non-histone proteins in addition to COX enzymes, though the specificity and physiological relevance of non-targeted protein acetylation remains under investigation. The acetylation of p53 at Lys382 by aspirin-derived acetyl groups has been demonstrated in cancer cell models, enhancing p53 transcriptional activity and pro-apoptotic gene expression independent of DNA damage signaling; this p53-activating mechanism may contribute to aspirin ability to promote apoptosis of pre-neoplastic cells in colon epithelium. These epigenetic findings are preliminary but consistent with the long latency and duration-dependent nature of aspirin cancer chemoprevention effects.

Clinical Evidence

Secondary Cardiovascular Prevention

The foundational secondary prevention evidence comes from the Antithrombotic Trialists Collaboration meta-analysis (BMJ 2002), which pooled 287 randomised trials in approximately 135,000 high-risk patients and found that antiplatelet therapy reduced the combined endpoint of serious vascular events (non-fatal MI, non-fatal stroke, vascular death) by approximately 25 percent. The analysis established the dose-equivalence of aspirin 75 to 150 mg daily with higher doses and showed that the number of serious vascular events prevented per 1,000 patients over 2 years (approximately 36) substantially exceeded the number of major extracranial bleeds caused (2 to 5).

For patients with prior MI, aspirin reduces recurrent MI by approximately 30 percent and vascular death by approximately 15 percent in long-term follow-up. After ischemic stroke or TIA, aspirin reduces recurrent stroke by approximately 23 percent. In peripheral arterial disease, aspirin reduces the combined endpoint of MI, stroke, and vascular death by approximately 25 percent over 2 years. These consistent secondary prevention benefits across all major atherosclerotic vascular territories have ensured guideline class I recommendation for aspirin 75 to 100 mg daily in all patients with established cardiovascular disease across ACC/AHA, ESC, and NICE guidelines.

The duration of secondary prevention aspirin is indefinite unless contraindicated or replaced by more potent antiplatelet agents in specific high-risk settings. Dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) is standard after ACS and coronary stenting for 6 to 12 months, after which aspirin monotherapy continues indefinitely.

Acute Coronary Syndrome

ISIS-2 (1988, n=17,187) remains the definitive trial establishing aspirin in acute MI. Aspirin 162.5 mg alone reduced five-week vascular mortality by 23 percent and non-fatal reinfarction by 49 percent; the combination with streptokinase reduced vascular mortality by 42 percent. The rapid onset of COX-1 inhibition within 30 minutes of a chewed or crushed plain aspirin dose is essential in the acute setting.

Current ACC/AHA and ESC ACS guidelines recommend 162 to 325 mg aspirin as soon as ACS is suspected, prior to any other antiplatelet administration. Following the acute phase, aspirin 81 to 100 mg daily is continued as maintenance therapy, combined with a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) for dual antiplatelet therapy. The duration of dual antiplatelet therapy is 6 to 12 months for ACS managed medically or with stenting, with ticagrelor or prasugrel preferred over clopidogrel in patients undergoing PCI for ACS due to superior MACE reduction in PLATO and TRITON-TIMI 38 respectively.

A critical clinical point: enteric-coated aspirin should not be used for the loading dose in ACS. Enteric coating delays aspirin dissolution and absorption by 3 to 4 hours, delaying the onset of platelet COX-1 inhibition in the setting where every minute of platelet inhibition matters. Plain aspirin or chewing a regular aspirin tablet achieves therapeutic platelet inhibition within 30 to 60 minutes.

Primary Cardiovascular Prevention

The 2018 publication of ASPREE, ARRIVE, and ASCEND simultaneously in a single week represented the most significant revision of aspirin prescribing evidence in decades. The three trials together enrolled 47,140 participants and collectively demonstrated that aspirin primary prevention benefit in low-to-moderate risk individuals is at best marginal and is outweighed by bleeding harms in most scenarios.

ASPREE (n=19,114, adults aged 70 or older) produced the most clinically consequential result: not only did aspirin fail to improve disability-free survival, but all-cause mortality was significantly higher in the aspirin group (HR 1.14, 95 percent CI 1.01 to 1.29), an unexpected finding driven by excess cancer deaths in the first three years. The cancer mortality signal in ASPREE is mechanistically plausible if aspirin promotes early cell death of pre-neoplastic clones that then release oncogenic material provoking tumour growth, though this interpretation remains speculative. ARRIVE (n=12,546, moderate cardiovascular risk) showed no MACE reduction with doubled GI bleeding. ASCEND (n=15,480, diabetes) showed a small vascular event reduction (RR 0.88) nearly perfectly counterbalanced by bleeding increase (RR 1.29).

The 2019 ACC/AHA primary prevention guideline response was explicit: aspirin should not be routinely initiated in adults over 70 for primary prevention; in adults aged 40 to 70 with elevated cardiovascular risk and no increased bleeding risk, aspirin may be considered after individualised discussion; and aspirin should not be initiated in adults with diabetes for primary prevention unless 10-year ASCVD risk is high enough to justify the modest absolute benefit over the bleeding risk. The USPSTF reached similar conclusions in 2022, recommending against initiating aspirin in adults over 60 and recommending a shared decision-making approach in adults aged 40 to 59 with high CVD risk.

Lynch Syndrome Cancer Chemoprevention

Lynch syndrome represents the clearest and most actionable indication for aspirin cancer chemoprevention. Carriers of germline MLH1, MSH2, MSH6, PMS2, or EPCAM mutations have lifetime colorectal cancer risks of 25 to 75 percent and significant extracolonic cancer risks (endometrial, ovarian, urinary tract, gastric). Standard surveillance involves colonoscopy every 1 to 2 years, but pharmacological chemoprevention was lacking until the CAPP2 trial.

CAPP2 (Lancet 2011, n=861) randomised Lynch syndrome carriers to aspirin 600 mg daily versus placebo in a two-by-two factorial design also including resistant starch. In the intention-to-treat analysis, aspirin showed a non-significant trend; in the per-protocol analysis of completers (two or more years of aspirin), CRC incidence was reduced by 63 percent (HR 0.37, 95 percent CI 0.18 to 0.78). Critically, the benefit appeared after aspirin cessation rather than during treatment, suggesting aspirin drove elimination of early pre-neoplastic clones rather than suppressing established tumours. The protective effect persisted for the full decade of post-randomisation follow-up.

CaPP3 (Lancet 2022, n=1,979) was a dose-finding trial comparing 100 mg, 300 mg, and 600 mg aspirin daily in Lynch syndrome carriers. All three doses produced similar reductions in CRC incidence with no statistical evidence of a dose-response relationship, establishing 100 mg daily as the preferred dose based on equivalent efficacy and substantially better GI tolerability. NCCN, European Lynch syndrome guidelines, and multiple oncology societies now recommend aspirin 75 to 100 mg daily for all Lynch syndrome carriers, with initiation recommended at age 25 to 30 years.

Cancer Prevention in the General Population

Beyond Lynch syndrome, Rothwell et al. (Lancet 2011, individual patient data from 8 randomised trials, n=25,570) demonstrated that daily aspirin reduced cancer mortality by 21 percent over 20 years, with effects becoming apparent after 5 years of use and applying across colorectal, lung, esophageal, and prostate cancers. A companion analysis (Lancet 2012) found that 3 or more years of daily aspirin reduced 20-year risk of cancer incidence by 24 percent (all solid tumours) and cancer deaths by 37 percent.

The latency before cancer prevention benefit onset (5 or more years) limits practical utility in short-lived populations and means the cancer prevention benefit cannot offset the bleeding risk in elderly individuals who have less than 10 years of remaining benefit window. In average-risk populations, the number needed to treat for cancer prevention is approximately 100 to 150 over 10 years, making population-wide aspirin chemoprevention of cancer an unfavourable benefit-harm trade-off outside high-risk groups.

The ASPREE cancer mortality finding, which showed increased cancer deaths in elderly aspirin users in the first three years, remains incompletely explained. One hypothesis is that aspirin suppresses immune surveillance in established micrometastatic disease, allowing occult tumours to escape; another is that aspirin-mediated tumor cell death releases inflammatory signals that promote metastatic dissemination in individuals with subclinical cancer. Neither the benefit nor the ASPREE signal fully explains the other, and the safest interpretation is that aspirin cancer chemoprevention is age-dependent: benefit likely predominates in younger individuals with intact cancer surveillance, while harm may predominate in older individuals with higher prevalence of subclinical disease.

Adverse Effects in Long-Term Trials

Gastrointestinal bleeding is the most clinically significant adverse effect of long-term aspirin therapy. In trial data, low-dose aspirin increases upper GI bleeding risk 2 to 4-fold compared to placebo, translating to approximately 1 to 3 excess GI bleeds per 1,000 patients per year in primary prevention settings. Risk factors for aspirin-associated GI bleeding include age over 65, prior peptic ulcer disease or GI bleeding history, H. pylori infection, concurrent NSAID use, concurrent anticoagulant or corticosteroid use, and SSRI use.

Intracranial hemorrhage is increased by approximately 0.2 per 1,000 patients per year with aspirin, a smaller absolute risk than GI bleeding but with higher case fatality. This intracranial hemorrhage risk is the primary driver of the unfavorable benefit-harm ratio in elderly primary prevention populations where baseline hemorrhagic stroke risk is higher.

The unexpected cancer mortality signal in ASPREE (HR 1.14 for all-cause mortality, driven by cancer deaths in the first 3 years) has not been reproduced in younger populations and remains under investigation. It has been proposed that aspirin in individuals with undetected subclinical cancers may promote dissemination through immune modulation of the tumour microenvironment, though this hypothesis requires prospective testing. Pending clarification, the signal reinforces against initiating aspirin in adults over 70 without a specific secondary prevention indication.

Renal effects include transient reduction in GFR in volume-depleted individuals and the rare aspirin-associated acute kidney injury in patients on triple therapy (RAAS inhibitor, diuretic, NSAID/aspirin). Hypersensitivity reactions occur in approximately 0.3 to 0.9 percent of the general population and in 10 to 20 percent of aspirin-sensitive asthmatics.

Longevity and Off-Label Evidence

Aspirin is not a recommended longevity intervention for the general population, and the ASPREE results provide a specific safety signal against initiating aspirin in adults over 70 without a prior cardiovascular event. However, several mechanistic and clinical strands position aspirin as pharmacologically relevant to longevity pathways.

The salicylate-AMPK mechanism identified by Hawley et al. (Science 2012) connects aspirin to the same energy-sensing kinase activated by metformin, exercise, and caloric restriction. Downstream of AMPK activation, salicylate suppresses mTORC1 through the AMPK-TSC2-Rheb axis, induces autophagy, and reduces NF-kappaB-driven inflammaging. These are the same pathways most strongly implicated in longevity biology across model organisms. Whether these pathway effects translate to meaningful lifespan extension in humans at antiplatelet doses remains undemonstrated.

The most compelling off-label aspirin application supported by randomised evidence is pre-eclampsia prevention (ASPRE trial), where aspirin 150 mg nightly from the first trimester reduces preterm pre-eclampsia by 62 percent in high-risk women, and this is now guideline-endorsed by ACOG, USPSTF, and NICE. For Lynch syndrome, aspirin 75 to 100 mg daily is standard of care based on CAPP2 and CaPP3 data, though “off-label” framing applies in jurisdictions where aspirin cancer chemoprevention is not an FDA-approved indication.

Aspirin is inexpensive (generic 81 mg, approximately 2 to 5 USD per month), globally accessible, and has over a century of safety data. These characteristics make it an attractive candidate for population-level longevity interventions if net benefit can be demonstrated in appropriately selected populations. The ongoing NovASA trial and updated USPSTF analyses may provide additional clarity on age-stratified primary prevention benefit, but current evidence supports aspirin only in the specific indications outlined above.

Dosing Guidance

For secondary cardiovascular prevention (post-MI, post-ischemic stroke, post-TIA, PAD, stable angina): aspirin 75 to 100 mg once daily, continued indefinitely. Doses above 100 mg daily are not more effective and substantially increase bleeding; 81 mg is the standard US practice.

For acute coronary syndrome: 162 to 325 mg loading dose immediately, using plain (non-enteric-coated) aspirin chewed or crushed for rapid absorption; followed by 81 mg daily maintenance combined with a P2Y12 inhibitor for 6 to 12 months.

For Lynch syndrome cancer chemoprevention: 75 to 100 mg daily starting at age 25 to 30; continue indefinitely unless a contraindication develops; CaPP3 confirms equivalent efficacy to 600 mg.

For pre-eclampsia prevention in high-risk pregnancies: 75 to 162 mg daily (150 mg nightly used in ASPRE) starting at 12 to 16 weeks gestation; discontinue at 36 weeks gestation.

For analgesia and antipyresis: 325 to 650 mg every 4 to 6 hours as needed; maximum 4 g per day in healthy adults.

For anti-inflammatory therapy in rheumatoid arthritis or other inflammatory arthritides (largely historical, now largely displaced by selective NSAIDs and DMARDs): 3 to 4 g per day in divided doses; monitor salicylate levels if tinnitus develops (target below 200 mg/L).

Dose adjustment for renal impairment: at eGFR below 50 mL/min/1.73m2, avoid regularly scheduled NSAID doses; antiplatelet dosing at 81 mg daily is generally acceptable down to eGFR of 10 mL/min/1.73m2 with monitoring. At eGFR below 10, avoid. No hepatic dose adjustment for antiplatelet doses; high-dose anti-inflammatory aspirin requires caution in severe hepatic impairment due to reduced salicylate metabolism and bleeding risk from coagulopathy.