Rapamycin supplements: what the science actually says

Rapamycin extended mouse lifespan by 26%. No other drug has come close to that number in a rigorous, independently replicated study. That's not hype. That's the National Institute on Aging's Interventions Testing Program, tested simultaneously at three independent labs, in genetically diverse mice, published in peer-reviewed journals.

And yet most people searching for "rapamycin supplements" end up confused, because rapamycin isn't a supplement. It's a prescription drug. So what ARE the supplement options? What's the difference between pharmaceutical rapamycin and the berberine-quercetin stacks marketed as "natural mTOR inhibitors"? And who should even be thinking about this?

This post covers all of it. The mechanism, the evidence, the risks, the alternatives, and what you can realistically do with this information today.

What is rapamycin?

Rapamycin has one of the more interesting origin stories in pharmacology. In 1964, a Canadian medical expedition traveled to Easter Island (Rapa Nui in the indigenous Polynesian language). They collected soil samples. A decade later, Surendra Nath Sehgal isolated a compound from those samples, produced by a bacterium called Streptomyces hygroscopicus. The compound had antifungal properties, and he named it after the island: rapamycin.

The anti-aging implications weren't on anyone's radar for decades. Rapamycin was developed as an immunosuppressant for organ transplant patients, where it's still used today (brand name Rapamune, generic name sirolimus). The longevity story came much later, when researchers started understanding what rapamycin was actually doing inside cells.

The FKBP12-mTOR mechanism

Here's how it works at the molecular level. Rapamycin enters cells and binds to a protein called FKBP12. This drug-protein complex then latches onto a specific domain of another protein called mTOR, mechanistic target of rapamycin. Specifically, it inhibits a complex called mTORC1.

mTOR is one of the most conserved proteins in biology. It exists in essentially every animal that has ever been studied, which tells you it does something important. What it does: it acts as a master sensor for nutrients, energy, and growth signals. When nutrients are abundant, mTOR ramps up protein synthesis, promotes cell growth, and suppresses cellular maintenance processes. When nutrients are scarce, mTOR quiets down and cells shift into repair and recycling mode.

The problem is that as we age, mTOR activity tends to stay chronically elevated even when we're not eating. And chronically elevated mTOR is one of the hallmarks of biological aging. It suppresses autophagy (the cellular housekeeping process that clears out damaged proteins and organelles), accelerates cellular senescence, and drives age-related inflammation.

By inhibiting mTOR, rapamycin essentially fools cells into thinking they're in a caloric restriction state. Autophagy ramps up. The body shifts from growth mode to maintenance mode. And in animal studies, this consistently extends healthy lifespan.

mTORC1 vs. mTORC2

One nuance matters a lot for understanding side effects. mTOR exists in two distinct complexes: mTORC1 and mTORC2. Rapamycin primarily hits mTORC1, which is the longevity target. But at higher doses or with continuous use, it also suppresses mTORC2, which regulates glucose metabolism and insulin signaling.

This is why transplant patients on daily high-dose rapamycin get insulin resistance and other metabolic problems. The longevity research community has figured out that intermittent, weekly dosing appears to target mTORC1 while allowing mTORC2 to recover between doses. Same mechanism, much better side effect profile.

That distinction, continuous vs. pulsed, is the central insight behind how researchers and physicians are actually using rapamycin for longevity today.

The animal evidence: what made rapamycin famous

The 2009 paper in Nature is where everything changed. Harrison and colleagues fed rapamycin to mice starting at 600 days of age, which is roughly equivalent to a 60-year-old human. Median lifespan increased 14% in females and 9% in males. The key part: this was done simultaneously at three independent testing sites, with genetically heterogeneous mice designed to avoid strain-specific flukes.

That was the first drug ever demonstrated to extend lifespan in mammals. MIT Technology Review called it exactly that. The scientific community took notice.

Later studies with higher doses and earlier start times produced bigger numbers. When rapamycin was started at 9 months (middle age), median survival increased 23% in males and 26% in females. These are the headline numbers you see cited most often in longevity circles. And the effect was dose-dependent: more rapamycin, more lifespan extension, across a range of doses.

It gets more interesting. A 2016 paper in eLife showed that just three months of rapamycin treatment in middle-aged mice extended both lifespan and healthspan. You didn't have to take it forever. A transient exposure in midlife was enough to shift the biological trajectory.

No other drug has this track record in the NIA's Interventions Testing Program. Acarbose works but only well in males. 17-alpha estradiol is males only. Rapamycin is the only compound that has consistently extended lifespan in both sexes across multiple independent replication attempts.

Does this translate to humans? That's the honest, hard question. Mice live 2-3 years. Humans live 80+ years. The processes governing aging differ between species. The animal data is extraordinary and justifies serious scientific interest. It doesn't prove rapamycin will extend human lifespan. Anyone who tells you it does is overreading the evidence.

The human evidence: what we actually know

The human data is early. But it's real, and it's encouraging in specific areas.

The Kaeberlein survey (2023)

Matt Kaeberlein at the University of Washington has been one of the leading scientific proponents of rapamycin for longevity. His team published a survey of 333 adults taking rapamycin off-label (median age 61, 78% male, median 218 days of use) compared to 172 non-users.

The headline finding: the only side effect significantly more common in rapamycin users was mouth ulcers. That's the whole list of increased negative effects. Meanwhile, six conditions were significantly less frequent in rapamycin users: abdominal cramps, depression, abdominal pain, muscle tightness, anxiety, and eye pain. And 44.7% of users reported improvement in overall health.

There's also a COVID-19 finding worth noting. Continuous rapamycin users had the lowest rate of moderate or severe infection in the study, 13.5% moderate with zero hospitalizations, compared to 3.7% severe in non-users.

This is a survey, not a randomized controlled trial. Selection bias is real. People self-selecting into taking a longevity drug are probably health-conscious in other ways. But it's the largest real-world dataset on off-label human use, and the safety signal is much better than transplant-dose literature would suggest.

The PEARL trial (2024)

The Participatory Evaluation of Aging with Rapamycin for Longevity trial was the first randomized, double-blind, placebo-controlled trial of rapamycin for longevity in healthy adults. 114 participants aged 50-85. Three arms: 5 mg/week compounded rapamycin, 10 mg/week compounded rapamycin, or placebo, for 48 weeks.

The primary endpoint, visceral fat reduction, didn't reach significance in any group. But the secondary findings were interesting. Women on 10 mg gained significant lean tissue mass at both 24 and 48 weeks. Women on 10 mg also reported significant reductions in pain. Men on 10 mg had an average 1.4% increase in bone mineral content over 48 weeks. Safety was similar across all groups, with canker sores as the most common side effect at about 20% of users.

One critical detail from the trial: the compounded rapamycin they used had about one-third the bioavailability per milligram of commercial formulations. So the "5 mg" arm was effectively closer to 1.5 mg equivalent, and the "10 mg" arm to 3 mg. This is important for interpreting the results and for understanding why effects may have been modest.

The immune rejuvenation studies

Back in 2014, a Novartis-funded study tested RAD001 (everolimus, a rapamycin analog) in elderly volunteers. At low doses, it enhanced flu vaccine response by approximately 20% compared to placebo and reduced markers of immune aging. This immune-related benefit is probably the most robustly replicated finding in human rapalog research.

A 2023 systematic review in Lancet Healthy Longevity surveyed the full landscape of human rapamycin and rapalog studies. Conclusion: improvements in immune, cardiovascular, and skin systems, but not in endocrine, muscular, or neurological systems. Limited evidence, but not nothing.

The honest assessment: rapamycin has some of the best animal data ever produced for a longevity intervention, and early human data in immune function and a few other domains looks promising. But nobody has shown it extends human lifespan, and no adequate-powered human trial exists yet. You're betting on the preclinical data while the human evidence catches up.

Who's actually taking it?

The longevity community has been running what amounts to a distributed self-experiment for several years now. Here's what the key figures have concluded.

Peter Attia takes 8 mg once weekly as of late 2023. He's been one of the most vocal physician proponents, discussing it extensively on his podcast. His framing is honest: the animal data is extraordinary, the human data is early, the side effect profile at weekly pulsed dosing looks acceptable, and he's made a personal decision to take it. He doesn't oversell it.

Bryan Johnson ran a five-year rapamycin experiment, escalating doses from 5 mg/week all the way to biweekly 13 mg protocols. In September 2024, he stopped entirely. His conclusion: "the benefits of lifelong dosing of rapamycin do not justify the hefty side effects." He documented intermittent skin and soft tissue infections, lipid abnormalities, glucose elevations, and increased resting heart rate. His experience is now widely cited in academic literature as a cautionary illustration of documented toxicities at higher doses and aggressive protocols.

The broader community is active. The Kaeberlein survey found 77-82% of off-label users were under physician supervision. The rapamycin.news forum has thousands of self-experimenters sharing data. The average user takes roughly 6 mg once weekly, which has become the de facto community consensus starting point.

If you want a personalized longevity protocol that factors in your biomarkers, goals, and current stack, WinAging's AI protocol builder can help you think through where rapamycin or its alternatives might fit.

Rapamycin is a prescription drug, not a supplement

This is the core fact that trips people up. Rapamycin (sirolimus) is an FDA-approved pharmaceutical. It's a Schedule H drug in most countries. You cannot buy it at a supplement store, on Amazon, or from any legitimate OTC source.

Everything sold as "rapamycin supplement" or "natural rapamycin" is either:

1. A compound that modulates the mTOR pathway (berberine, quercetin, fisetin, resveratrol) but is dramatically weaker than pharmaceutical rapamycin
2. Something falsely labeled, which is a safety hazard

This matters because the marketing around "natural mTOR inhibitors" often implies equivalence with the drug. It's not equivalent. The animal data showing 23-26% lifespan extension is for pharmaceutical rapamycin at specific doses. No natural compound has replicated that in the same rigorous experimental framework.

That said, natural mTOR modulators are real, have real evidence, and are a legitimate part of a longevity supplement stack. They're just not rapamycin.

How to access prescription rapamycin

All legitimate access to rapamycin for longevity purposes goes through a physician who prescribes it off-label (aging is not classified as a disease, so there's no FDA-approved indication for longevity use). The options:

Primary care or longevity physician. If your doctor is familiar with the research and willing to prescribe, you can get a prescription for generic sirolimus at a standard pharmacy. With GoodRx coupons, generic sirolimus runs about $66-100 per month for typical longevity doses (6-8 mg/week equals 24-32 mg/month). At retail price without discounts, it's dramatically more expensive, so always use a discount card.

Longevity telehealth platforms. Services like AgelessRx and similar platforms connect patients with physicians who specialize in off-label longevity prescriptions. Costs run $124 to over $700 per six-month cycle, including physician consultation and platform fees. Convenient but potentially more expensive than the pharmacy route once physician access is established.

Compounding pharmacies. Some longevity clinics and physicians prescribe compounded rapamycin capsules. Key point: compounded versions have approximately one-third the bioavailability of commercial sirolimus per milligram. A 10 mg compounded capsule is roughly equivalent to a 3 mg commercial tablet. This is established from the PEARL trial analysis. Higher nominal doses are typically prescribed to compensate.

Brand name Rapamune vs. generic sirolimus. These are pharmacologically equivalent per FDA standards. Generic is far cheaper. For longevity use, generic sirolimus at a standard pharmacy with a discount card is usually the most cost-effective and pharmacokinetically reliable option.

Use the supplement interaction checker to verify your current stack before adding anything to it.

Dosing protocols: what researchers and physicians actually use

No standardized protocol exists. No FDA-approved dosing for longevity exists. Everything below is based on: animal models, the Kaeberlein survey, the PEARL trial, and physician experience. Anyone taking rapamycin for longevity is participating in an ongoing uncontrolled experiment.

That said, there's enough data to identify a reasonable approach.

Weekly pulsed dosing is the consensus. Taking rapamycin once a week rather than daily allows mTORC2-related pathways to recover between doses. This preserves the longevity benefits (mTORC1 inhibition, autophagy induction) while substantially reducing metabolic side effects. The mouse data also showed intermittent dosing (one month on, one month off) was as effective as continuous dosing in males.

The most common dose: 6 mg once weekly. The Kaeberlein survey found 88% of off-label users took weekly doses, with 6 mg being the most common single dose. Peter Attia takes 8 mg weekly. The PEARL trial used 5 mg and 10 mg compounded (approximately 1.5 mg and 3 mg equivalent).

Start low and titrate up. Most practitioners start at 2-3 mg weekly and increase by 1-2 mg every few weeks based on tolerance. Mouth ulcers are the key signal: if you get them, you've likely hit your dose ceiling. Reduce the dose and they typically resolve.

Drug holidays. Some practitioners take 2-4 week breaks every few months to further reduce any cumulative mTORC2 suppression. There's no solid evidence base for optimal holiday frequency; it's more precautionary reasoning.

The practical reality: if you're going to take rapamycin, you need a physician partner who understands the research and can monitor your labs (lipids, glucose, HbA1c, complete blood count) every 3-6 months. This is not a compound to use without medical oversight.

Side effects and safety: the honest picture

At transplant doses (daily, 5-10+ mg continuously), rapamycin causes significant immunosuppression, insulin resistance, dyslipidemia, wound healing impairment, and a range of other problems. That's the side effect profile that most people find when they search the drug.

At longevity doses (weekly pulsed, 2-8 mg), the picture is considerably better but not without risk.

What's clearly seen at longevity doses:

Mouth ulcers affect roughly 20% of users and are the most consistent dose-dependent side effect. They're uncomfortable but manageable and signal you've hit your dose ceiling.

Glucose and HbA1c elevations appear at higher doses in some users. The PEARL trial found small HbA1c increases in males on 5 mg (effective 1.5 mg equivalent). Related to some mTORC2 suppression. Monitor with labs.

Lipid changes including elevated LDL and triglycerides are documented. Less consistent at weekly doses than at daily doses but worth monitoring.

Increased infection susceptibility is mechanistically expected (mTOR plays a role in immune function) and tracked in studies, though the Kaeberlein survey didn't find this reached statistical significance at typical longevity doses.

Impaired wound healing is a documented mechanism. Pause rapamycin before any surgery or significant wound.

What's NOT well established at longevity doses:

The testicular and ovarian effects documented in mice given continuous high doses. The muscle wasting and immune collapse seen in transplant patients. These appear to be dose and frequency dependent, not inherent to mTOR inhibition at any dose.

The muscle question deserves its own paragraph. mTORC1 is required for post-exercise muscle protein synthesis. Rapamycin blocks it. A published study confirmed rapamycin blocks contraction-induced skeletal muscle protein synthesis in humans. This is a real concern, particularly for younger people focused on building muscle. But here's the paradox: aging itself causes chronically dysregulated, elevated mTOR in muscle, which paradoxically impairs muscle function. Research from the Glass Lab found rapamycin actually reversed sarcopenia in aged animals by correcting this aberrant signaling. The practical takeaway: the muscle risk may be more relevant for younger users optimizing for hypertrophy than for older adults dealing with age-related muscle dysfunction.

Drug interactions you must know

This section matters a lot. Rapamycin has some interactions that can be dangerous, and one of them is something millions of people consume casually.

Grapefruit and grapefruit juice: absolutely contraindicated. Grapefruit irreversibly inhibits CYP3A4, the liver enzyme that metabolizes sirolimus. Eating grapefruit within 24-72 hours of taking rapamycin can dramatically elevate blood levels, potentially to toxic concentrations. This isn't a minor caution. Avoid grapefruit completely while taking rapamycin.

CBD (cannabidiol): significant interaction. CBD is a potent CYP3A4 inhibitor. Given how widely CBD products are used (gummies, oils, topicals, drinks), this interaction is a major practical concern. CBD can significantly raise rapamycin blood levels and increase toxicity risk. If you're using CBD regularly, discuss this with your prescribing physician.

Other CYP3A4 inhibitors. Ketoconazole, itraconazole, erythromycin, and clarithromycin all raise rapamycin levels. CYP3A4 inducers like rifampin decrease rapamycin effectiveness. Review all medications with your physician before starting.

St. John's Wort. A potent CYP3A4 inducer. Significantly reduces rapamycin levels and could eliminate the longevity effect.

Before starting rapamycin, check your entire supplement stack using the WinAging interaction checker. And tell your prescribing physician everything you're taking.

Natural rapamycin alternatives: the mTOR modulator supplement stack

This is what most people searching for "rapamycin supplements" are actually looking for: legal, over-the-counter compounds that modulate the mTOR pathway.

None of these are rapamycin. None have produced 23-26% lifespan extension in the ITP. But they do have real biological activity, real evidence, and legitimate roles in a longevity supplement stack. The key is having accurate expectations.

Berberine. The most studied natural mTOR modulator. Berberine activates AMPK (AMP-activated protein kinase), which is essentially the energy sensor that opposes mTOR. When AMPK is active, mTOR is suppressed. A 2019 study published in Aging found berberine functions as an mTOR inhibitor that reduces the generation of senescent cells and extended lifespan in mice. It's dramatically weaker than rapamycin but accessible (500-1500 mg/day), inexpensive ($15-30/month), and has extensive research supporting glucose and metabolic health benefits as well. Berberine's synergistic effects make it one of the most versatile compounds in a longevity stack.

Fisetin. A polyphenol found in strawberries, apples, and cucumbers. Acts as both a senolytic (clears senescent cells) and mTOR modulator. Has extended lifespan in mouse studies and has an active Phase 2 clinical trial examining its effects on frailty and inflammation in older adults. Typical studied doses: 100-500 mg/day, sometimes used in 2-3 day monthly "fisetin pulses" rather than daily dosing.

Quercetin. Often paired with fisetin or dasatinib in senolytic protocols. Inhibits mTOR signaling, has anti-inflammatory properties, and has some human data in the context of senolytic therapy. Typical longevity doses: 500-1000 mg/day. The differences between quercetin forms matter for absorption, so bioavailability is worth considering.

Resveratrol. Activates SIRT1, which can inhibit mTOR and promote autophagy, mechanistically overlapping with rapamycin's effects. Absorption issues are real with standard resveratrol, micronized or trans-resveratrol with fat improves this. Comparing resveratrol vs. NMN is a common question for longevity enthusiasts building their stack.

Spermidine. A polyamine found in aged cheese, fermented foods, and wheat germ that induces autophagy through mTOR-adjacent pathways. Has human observational data linking higher dietary spermidine intake to lower cardiovascular mortality. Not directly an mTOR inhibitor but activates similar cellular maintenance pathways.

Caloric restriction and fasting. The original mTOR inhibitor. mTOR is a nutrient sensor, and removing nutrients shuts it down. Time-restricted eating and periodic prolonged fasting are the most accessible "rapamycin mimetics" with the broadest human evidence base. The argument for combining fasting with berberine or other mTOR modulators is that you're hitting the same pathway through multiple angles.

The "natural rapamycin stack" concept

Some longevity practitioners stack berberine, fisetin, quercetin, and periodic fasting together as a supplement protocol intended to approximate some of rapamycin's mechanism without the prescription drug. There's no head-to-head comparison, and the magnitude of effect is certainly smaller. But the logic is mechanistically sound.

If you're not a candidate for prescription rapamycin, or you're early in your longevity journey and want to start with proven, accessible interventions, this kind of natural mTOR modulator stack is where to start. WinAging's AI protocol builder can help you design a personalized stack based on your age, goals, and biomarkers.

Is rapamycin right for you?

Honest answer: probably not for most people reading this, yet.

Rapamycin requires physician oversight and monitoring. The human evidence base, while encouraging, is still early. Side effects at longevity doses are manageable but real. And the compounds most likely to prescribe it off-label are still relatively rare, though longevity telehealth has made access more feasible.

Who might reasonably consider it:

You're 50+ and already doing the fundamentals (sleep, exercise, metabolic health, diet). You've worked through the accessible supplement stack. You have a physician willing to monitor you. You understand the evidence is preclinical-heavy and you're comfortable with that uncertainty. And you're not using CBD regularly, eating grapefruit, or taking other CYP3A4 inhibitors.

Who should not be taking it:

Anyone with active infections, immune compromise, uncontrolled diabetes, planned surgery, or who is pregnant or breastfeeding. Anyone on strong CYP3A4 inhibitors without physician coordination.

Use the biological age calculator to get a baseline on where you're starting from. That number helps you prioritize where to focus first.

The more important question for most people: have you optimized the fundamentals? Sleep quality, resistance training, metabolic health, and the well-researched supplement stack (NMN or NR, berberine, spermidine, fisetin, quercetin) all have meaningful evidence and far lower barriers to access. These aren't consolation prizes. They're the foundation that makes any advanced intervention actually work.

Frequently asked questions

Is rapamycin available as an over-the-counter supplement?

No. Rapamycin (sirolimus) is a prescription drug. Products marketed as "rapamycin supplements" or "natural rapamycin" are either natural mTOR inhibitors like berberine and quercetin (which work through similar pathways but are dramatically weaker) or are mislabeled. Legitimate rapamycin access requires a physician prescription, either through a primary care doctor familiar with the research or through longevity telehealth platforms.

What's the best natural alternative to rapamycin?

Berberine is the most studied and accessible natural mTOR modulator. It activates AMPK, which suppresses mTOR signaling, and has a 2019 mouse study showing lifespan extension through this mechanism. At 500-1500 mg/day, it's also one of the most affordable longevity compounds available. Fisetin and quercetin work through senolytic and mTOR-modulating pathways as well. Combining these with intermittent fasting, which directly suppresses mTOR by removing the nutrient signal it responds to, gives you the most comprehensive natural approach.

What dose of rapamycin do longevity researchers use?

The most common off-label longevity dose based on the Kaeberlein survey (333 adults) is 6 mg once weekly. Peter Attia uses 8 mg once weekly. The PEARL trial tested 5 mg and 10 mg weekly compounded formulations (equivalent to about 1.5 mg and 3 mg of commercial sirolimus due to lower bioavailability). There's no standardized protocol. Physicians typically start patients at 2-3 mg weekly and titrate up based on tolerance.

Did Bryan Johnson stop taking rapamycin?

Yes. Bryan Johnson discontinued rapamycin in September 2024 after approximately five years and various dose escalation experiments. His stated reason: the benefits didn't justify the side effects, which included intermittent skin and soft tissue infections, lipid abnormalities, glucose elevations, and increased resting heart rate. His experience is worth noting but also reflects more aggressive dosing protocols than most practitioners recommend. Peter Attia continues taking it at 8 mg weekly.

Can you take rapamycin with berberine?

There's no known dangerous interaction between rapamycin and berberine. Both inhibit mTOR through different mechanisms (rapamycin directly via FKBP12, berberine indirectly via AMPK activation), so combining them would theoretically be synergistic. Some physicians do prescribe rapamycin alongside natural mTOR modulators. That said, always use the supplement interaction checker and discuss your full stack with your prescribing physician. Monitoring labs are important when combining multiple interventions that affect similar pathways.

What are the side effects of rapamycin for longevity?

At typical longevity doses (weekly pulsed, 2-8 mg), the most common side effect is mouth ulcers, affecting roughly 20% of users in the PEARL trial. Some users experience elevated blood glucose, lipid changes, or increased susceptibility to minor infections. Wound healing can be impaired, so rapamycin should be paused before surgery. The severe side effects seen in transplant patients (significant immunosuppression, insulin resistance, dyslipidemia) are associated with daily high-dose use, not the weekly pulsed protocols used for longevity. Monitoring labs every 3-6 months is recommended.

How much does rapamycin cost for longevity use?

Generic sirolimus at a standard pharmacy with a GoodRx discount card typically runs $66-100 per month for longevity doses (24-32 mg/month for 6-8 mg weekly dosing). Longevity telehealth platforms charge $124 to over $700 per six-month cycle including physician fees. Compounded versions vary by pharmacy but require higher nominal doses to compensate for approximately one-third lower bioavailability. More details on rapamycin cost and how to access a prescription are covered in dedicated guides.

Related guides

• Rapamycin cost: what you'll actually pay
• How to buy rapamycin: prescription access explained
• Berberine synergy: best combinations for longevity
• Resveratrol or NMN: which should you take?
• Supplement interaction checker

Sources

• Harrison et al., Rapamycin fed late in life extends lifespan in mice (Nature, 2009)
• Kaeberlein et al., Evaluation of off-label rapamycin use in 333 adults (GeroScience, 2023)
• PEARL Trial results (PMC, 2024)

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The animal data on rapamycin is genuinely remarkable. A 26% increase in median lifespan, replicated independently, in mammals, starting in middle age. Nothing in longevity research comes close to that number. The human evidence is real but early. And the natural mTOR modulator stack (berberine, fisetin, quercetin, caloric restriction) represents a legitimate, accessible starting point for anyone who can't or won't take the prescription drug.

Start with the fundamentals. Work up to the advanced interventions as the evidence matures and as your own biomarkers give you a clearer picture of where your biology needs support. Build your personalized protocol or explore the free longevity tools to figure out where you actually stand.