Episode 107
GLP-1 Drugs, the Mediterranean Diet, and the Science of Living Longer
GLP-1 Drugs, the Mediterranean Diet, and the Science of Living Longer
For years, anti-aging has been hijacked by supplements, hacks, and promises that never hold up. Meanwhile, real science has quietly moved forward. Today, the most compelling anti-aging story does not come from a powder, a cold plunge, or a fasting app. Instead, it comes from metabolism.
A class of medications called GLP-1 receptor agonists started as diabetes drugs. Over time, clinicians discovered something bigger. These medicines now play a major role in obesity treatment, and they produce effects that reach far beyond the scale. Because obesity shortens lifespan and damages nearly every organ system, it makes sense that drugs that treat obesity could also improve healthspan—the years you live with strength, clarity, and independence.
However, weight loss alone does not explain what researchers are seeing. These drugs reduce inflammation, protect the heart, lower biological stress, and may even delay cognitive decline. Importantly, many of these effects occur independent of weight loss. That fact has forced scientists to ask a serious question: could GLP-1 drugs represent a new class of anti-aging medicine?
Even longevity-focused clinicians, such as Peter Attia, have publicly discussed using GLP-1 drugs at lower doses in select patients—not for weight loss, but for metabolic health and long-term disease prevention.
Why Metabolism Matters for Aging
Aging is not just about time. Instead, it reflects how well your body regulates key systems over decades. Blood sugar control, inflammation, oxidative stress, and cellular repair all shape how fast—or how slowly—you age.
GLP-1 receptor agonists influence all these pathways. Originally designed to mimic a gut hormone that signals fullness, these drugs turned out to do much more. Research shows they lower systemic inflammation, improve mitochondrial function, and reduce oxidative stress. As a result, organs function better for longer.
In simple terms, when metabolism runs smoothly, cells behave younger.
Retatrutide and the Next Generation of GLP-1 Drugs
Newer drugs have taken this concept even further. Retatrutide, a triple-agonist medication, targets three hormonal pathways simultaneously: GLP-1, GIP, and glucagon.
In Phase 3 trials, participants lost nearly 29% of their body weight, or more than 70 pounds on average. Yet weight loss only tells part of the story. Retatrutide also lowered inflammation, improved blood pressure, improved lipid profiles, and reduced joint pain.
Each hormone plays a role. GLP-1 reduces appetite and inflammation. GIP improves insulin sensitivity and nutrient handling. Glucagon increases energy expenditure and fat oxidation. Together, these pathways keep metabolism active, not slowing down during weight loss.
That combination does more than shrink waistlines. It restores metabolic flexibility, which declines with age.
Inflammation: The Engine of Aging
For decades, scientists blamed aging on simple wear and tear. Modern research tells a different story. Chronic, low-grade inflammation—often called inflammaging—drives many diseases of aging.
Heart disease, stroke, arthritis, fatty liver disease, and cognitive decline all share this inflammatory background. In clinical trials, GLP-1 drugs reduced markers such as C-reactive protein, triglycerides, and blood pressure. These changes signal reduced biological aging risk, not just better lab numbers.
When inflammation falls, fewer senescent cells accumulate. Blood vessels stay healthier. Organs function longer.
Heart Disease and Longevity
Nothing ages a person faster than a heart attack. Because of that reality, cardiovascular protection matters deeply for longevity.
Multiple cardiovascular outcome trials show that GLP-1 receptor agonists reduce major adverse cardiovascular events in people with type 2 diabetes and high cardiovascular risk. Across studies, researchers observed a 13% reduction in cardiovascular death and a 9% reduction in nonfatal heart attacks compared with other treatments.¹²
The LEADER trial demonstrated that liraglutide reduced cardiovascular mortality by 22%.⁶ Similar benefits appeared with semaglutide, dulaglutide, and albiglutide.²⁷ Because of this evidence, the FDA approved several GLP-1 drugs for cardiovascular risk reduction in adults with diabetes and established heart disease.⁸
These benefits do not come from glucose control alone. GLP-1 drugs lower blood pressure, reduce inflammation, improve endothelial function, decrease oxidative stress, and reduce RAAS activity.³⁴ At the cellular level, they protect heart muscle cells from multiple forms of cell death while enhancing autophagy and mitophagy.⁵
Although GLP-1 drugs do not strongly reduce heart failure hospitalizations, meta-analyses suggest a modest benefit.³⁷ Most importantly, they safely reduce atherosclerotic risk. Preventing a heart attack remains one of the most powerful anti-aging interventions available.
Dementia: Prevention, Not Cure
Brain health deserves careful discussion. GLP-1 drugs do not reverse dementia. They do not improve cognition once dementia is established. Recent trials in patients with Alzheimer’s disease showed no meaningful cognitive improvement.
That limitation matters.
However, prevention tells a different story. Large observational studies show that GLP-1 receptor agonists are associated with 33–45% lower dementia risk compared with other glucose-lowering drugs in people with type 2 diabetes.¹² A 2025 JAMA Neurology study involving nearly 34,000 patients found a 33% lower risk of Alzheimer’s disease and related dementias among GLP-1 users.¹
Randomized trial evidence shows a more modest, but still significant effect. A 2025 JAMA Neurology meta-analysis found that GLP-1 drugs reduced dementia risk, while SGLT2 inhibitors did not.³ This finding suggests a class-specific effect, rather than a glucose-only explanation.
Mechanistically, GLP-1 drugs reduce neuroinflammation, improve insulin signaling in the brain, promote neurogenesis, and may reduce amyloid-β and tau pathology.⁵⁶ They also improve vascular health, which strongly influences cognitive aging.
Age appears to matter. A 2025 target-trial emulation showed weaker effects in adults over 75, but stronger protection in younger patients.⁷ The takeaway remains clear: earlier prevention works better.
The goal is not to cure dementia. Instead, the goal is to delay its onset long enough that many people never reach it.
Ultra-Processed Food and Brain Aging
Diet still matters. Ultra-processed foods damage the same systems that GLP-1 drugs try to repair.
These foods hijack dopamine reward pathways, increase cravings, and weaken satiety signals. Soft textures and engineered flavors allow rapid overconsumption. High intake links to higher inflammation, worse metabolic health, reduced gray-matter density, and faster brain aging.
Additives and emulsifiers disrupt the gut microbiome and the gut-brain axis. As a result, insulin signaling in the brain worsens. GLP-1 drugs often counteract damage caused by this food environment, but prevention works better than repair.
The Mediterranean Diet and Alcohol
Here is the empowering part. People can act today.
The Mediterranean diet remains the dietary pattern with the strongest evidence for protecting both the heart and the brain. Vegetables, legumes, fruit, whole grains, olive oil, fish, and minimal ultra-processed food form its foundation. This pattern reduces inflammation, improves vascular health, supports the microbiome, and slows cognitive decline.
Think of it this way: GLP-1 drugs quiet the metabolic noise. The Mediterranean diet keeps it quiet.
Alcohol also matters. Earlier beliefs about alcohol and brain protection did not hold up. Even moderate drinking increases dementia risk, worsens sleep, raises inflammation, and damages the hippocampus. If cognitive protection matters, less alcohol helps, and none works best.
What This Means for Healthspan
Aging is not about adding years. Aging is about protecting systems.
GLP-1 drugs support metabolic health. The Mediterranean diet supports biology. Avoiding alcohol protects the brain. Movement and sleep reinforce everything else.
If heart disease, dementia, and disability are delayed long enough, many people will never experience them. That outcome does not represent immortality. Instead, it represents success at healthspan.
References
- Ussher JR, Drucker DJ. Glucagon-Like Peptide 1 Receptor Agonists: Cardiovascular Benefits and Mechanisms of Action. Nat Rev Cardiol. 2023;20(7):463–474.
- Nauck MA, et al. Cardiovascular Actions and Clinical Outcomes With GLP-1 Receptor Agonists. Circulation. 2017;136:849–870.
- Pop-Busui R, et al. Heart Failure: An Underappreciated Complication of Diabetes. Diabetes Care. 2022;45:1670–1690.
- Wu Q, et al. Glucose-Independent Cardiovascular Mechanisms of GLP-1 RAs. Biomed Pharmacother. 2022;153:113517.
- Boshchenko AA, et al. Cardioprotective Signaling of GLP-1 Receptor Agonists. Int J Mol Sci. 2024;25:4900.
- Marso SP, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311–322.
- Honka H, et al. Therapeutic Manipulation of Myocardial Metabolism. J Am Coll Cardiol. 2021;77:2022–2039.
- FDA Orange Book.
- Tang H, et al. GLP-1RA Medications and Dementia Risk. JAMA Neurol. 2025;82:439–449.
- Seminer A, et al. Cardioprotective Glucose-Lowering Agents and Dementia Risk. JAMA Neurol. 2025;82:450–460.
- Au HCT, et al. GLP-1 and Neurodegenerative Pathology. Neurosci Biobehav Rev. 2025;173:106159.
- Inoue K, et al. GLP-1 RAs and Dementia Incidence in Older Adults. Ann Intern Med. 2025.
Transcript
>> Dr. Terry Simpson: We talk a lot about aging, aging with good health,
Speaker:aging with a good health span and longevity. And
Speaker:we talk a lot about supplements that don't work or
Speaker:to diets that are rather silly. But today, the
Speaker:biggest anti aging story isn't in a pill or a cold
Speaker:plunge or a fasting app. Uh, it's in your
Speaker:metabolism. And it starts with a class of drugs we
Speaker:once thought were just for diabetes, the GLP1
Speaker:receptor agonists, you know, Ozempic, Zepbound,
Speaker:etc. These medications are now being primarily
Speaker:used for obesity. And they're doing remarkable
Speaker:things, not only reducing weight, but reversing
Speaker:many of the diseases that travel with and maybe
Speaker:because of obesity. And since obesity clearly
Speaker:shortens your health span, it's not surprising
Speaker:that these drugs are now being looked at as tools
Speaker:to improve health. Spanish the years you live
Speaker:well, not just lengthening a, uh, miserable life.
Speaker:But it turns out there is much more to these drugs
Speaker:than weight loss. These drugs have anti
Speaker:inflammatory effects, cardiovascular protection,
Speaker:reductions in stress physiology, and emerging
Speaker:evidence they may delay cognitive decline. And
Speaker:many of those benefits appear to be independent of
Speaker:weight loss. So the idea that GLP1 drugs, and now
Speaker:triple agonists like pitoutatride might represent
Speaker:a new class of anti aging medicine isn't hype.
Speaker:It's a serious scientific question. Even Peter
Speaker:Attia, whose clinic focuses almost exclusively on
Speaker:longevity and health span, has discussed using
Speaker:GLP1 drugs at lower doses in select patients to
Speaker:support metabolic health and long term health.
Speaker:Spanish this week, Eli Lilly released striking
Speaker:phase three data on their newest compound,
Speaker:retatrutide, a triple hormone drug that isn't just
Speaker:helping people lose weight. It may be resetting
Speaker:the biology of aging. Today on 4Q, we're going to
Speaker:make sense of the madness of Healthspan and GLP1.
Speaker:I am, um, your chief medical explanationist, Dr.
Speaker:Terri Simpson, and this is 4Q Fork University,
Speaker:where we bust myths, make sense of the madness,
Speaker:and teach you a little bit about food and
Speaker:medicine. When we talk about longevity, we're
Speaker:really talking about metabolic stability, blood
Speaker:sugar control, lower inflammation, lower oxidative
Speaker:stress, the ability of cells to repair. And GLP1
Speaker:agonists touch all of these systems. They were
Speaker:designed to mimic a gut hormone, the glucagon,
Speaker:like peptide 1, which signals satiety and improves
Speaker:glucose regulation. But over the last decade,
Speaker:we've learned they do far more than lower
Speaker:hemoglobin A1C and make diabetes better control.
Speaker:They reduce systemic inflammation, they improve
Speaker:mitochondrial efficiency, they lower oxidative
Speaker:stress, and they improve vascular function. The
Speaker:same biology that reduces appetite may also make
Speaker:cells behave younger. Enter UH retatrutide. In
Speaker:Lilly's Phase 3 Triumph 4 trial, participants lost
Speaker:nearly 29% of their body weight over 70 pounds on
Speaker:average, and saw UH major improvements in
Speaker:inflammation, blood pressure, lipids and joint
Speaker:pain. But weight loss is just the surface.
Speaker:Retatutride targets three key pathways. There's
Speaker:the GLP1 pathway, which reduces appetite and
Speaker:inflammation. There's the GIP, which improves
Speaker:insulin sensitivity and nutrient handling. And
Speaker:this one adds a glucagon, which increases energy
Speaker:expenditure and fat oxidation. If GLP1 calms the
Speaker:system and GIP balances it, glucagon fights a
Speaker:controlled metabolic fire, keeping metabolism from
Speaker:slowing down as weight is lost. That's not just
Speaker:slimming, that's metabolic rejuvenation. Let's
Speaker:talk about inflammaging. Aging isn't just wear and
Speaker:tear. It's driven by chronic low grade
Speaker:inflammation, where gerontologists call
Speaker:inflammaging. Inflammaging fuels heart disease,
Speaker:strokes, type 2 diabetes, fatty liver, arthritis
Speaker:and likely cognitive decline. In the Triumph 4
Speaker:trials, retatutride decreased CRP, triglycerides
Speaker:and blood pressure. Classic anti aging biomarkers.
Speaker:Less inflammation means fewer senescent cells,
Speaker:healthier blood vessels and better organ function.
Speaker:Let's talk about heart disease and GLP1s. And if
Speaker:you want to talk about aging, you have to talk
Speaker:heart disease because nothing ages you faster than
Speaker:a heart attack. Across multiple cardiovascular
Speaker:outcome trials, GLP1 receptor agonist, which is
Speaker:all these new drugs, have shown a 13% reduction in
Speaker:cardiovascular death, a uh, 9% reduction in non
Speaker:fatal heart attacks or myocardial infarctions. In
Speaker:the so called leader trials, liraglutide reduced
Speaker:cardiovascular mortality by 22%. Now semaglutide
Speaker:and lugotide show similar reductions, enough that
Speaker:the FDA now recognizes certain GLP1 drugs as
Speaker:cardiovascular red risk reducing therapies in
Speaker:patients with type 2 diabetes and established
Speaker:heart disease. These benefits are not just about
Speaker:sugar control. Turns out the GLP1s lower blood
Speaker:pressure, reduce inflammation, improve endothelial
Speaker:function. That's the cells that surround the
Speaker:vessels, reduce oxidative stress and decrease what
Speaker:we call RAS activation, which means at the
Speaker:cellular level they protect heart cell muscles
Speaker:from multiple forms of cell death and enhance
Speaker:autophagy and mitophagy. That means the heart is
Speaker:cleaning up old cells and old mitochondria. They
Speaker:don't dramatically treat heart failure the way
Speaker:SGLT2 inhibitors do, but they are safe and reduce
Speaker:atherosclerotic risk. Avoiding a heart attack is
Speaker:one of the most powerful anti aging interventions
Speaker:and powerful ways to increase your health span.
Speaker:People who live a long time aren't free from heart
Speaker:disease, but what they are free from is heart
Speaker:disease for a little while. Meaning healthspan
Speaker:puts it off.
Speaker:Now, let's talk about the brain. Let's be careful
Speaker:here. GLP1 drugs do not reverse dementia. They do
Speaker:not improve cognition once dementia is
Speaker:established. Recent trials in people with
Speaker:diagnosed Alzheimer's disease have shown no
Speaker:meaningful cognitive improvement. And that's
Speaker:critical for me to tell you that clearly the
Speaker:promise of GLP1 drugs is prevention and delay, not
Speaker:cure. And in large observational drugs, GLP1 users
Speaker:had roughly 33 to 45% lower risk of developing
Speaker:dementia compared with other diabetic drugs. The
Speaker:2025 Journal of the American Medical association
Speaker:of Neurology had a study that showed uh, a 33%
Speaker:lower risk of Alzheimer's and related dementias,
Speaker:especially in people who have cardiovascular
Speaker:disease. Randomized trial meta analysis show a
Speaker:real but m more modest protective signal stronger
Speaker:than what we actually see with other types of
Speaker:drugs. Mechanistically, GLP1s reduce
Speaker:neuroinflammation. That's inflammation of the
Speaker:brain. They improve insulin signaling in the
Speaker:brain, they enhance vascular health in the brain.
Speaker:They perform neurogenesis and they may reduce
Speaker:amyloid and tau pathology. Age matters. The
Speaker:benefit appear stronger when started earlier,
Speaker:before neurodegeneration is established. But our
Speaker:goal here is not immortality. The goal is to push
Speaker:dementia far enough into the future that many
Speaker:people never reach it. That's healthspan.
Speaker:Let's talk about ultra processed food and brain
Speaker:aging. This may be the real Ultra processed food
Speaker:isn't a terribly difficult concept, but you
Speaker:probably get the general idea. These foods hijack
Speaker:the brain's dopamine reward system, increasing
Speaker:wanting while reducing pleasure. They're soft,
Speaker:fast, hyperpalatable and engineered to be consumed
Speaker:before the gut can signal fullness. Ultra
Speaker:processed food intake is linked to higher
Speaker:inflammation, lower gray matter density, worse
Speaker:metabolic health and faster brain aging. They
Speaker:disrupt that gut brain access, damage the
Speaker:microbiome and worsen insulin signaling in the
Speaker:brain. GLP1 drugs are in many ways repairing
Speaker:damage caused by a food environment designed to
Speaker:exploit our biology. What about the Mediterranean
Speaker:diet and alcohol? Well now, here's the empowering
Speaker:part. If there is one dietary pattern with the
Speaker:strongest evidence for protecting the heart and
Speaker:the brain, it's the Mediterranean diet.
Speaker:Vegetables, legumes, fruit, whole grains, olive
Speaker:oil, fish. Minimally ultra processed food. This
Speaker:pattern reduces inflammation Supports the
Speaker:microbiome, um, improves vascular health and slows
Speaker:cognitive decline. GLP1 drugs calm the biology.
Speaker:The Mediterranean diet keeps it calm. And one more
Speaker:hard truth, we've talked about this before.
Speaker:Alcohol. The idea that alcohol protects the brain
Speaker:has never been held up. Even moderate drinking is
Speaker:associated with higher dementia risk, worse sleep,
Speaker:hippocampal injury and increased neuro
Speaker:inflammation. If your goal is to protect your
Speaker:brain, thus alcohol is better. No, alcohol is
Speaker:best. So what does this really mean now? Aging
Speaker:isn't about the years, it's about systems. GLP1
Speaker:drugs support metabolism. The Mediterranean diet
Speaker:supports biology. Avoiding alcohol protects the
Speaker:brain and the heart and the kidneys and the eyes,
Speaker:movement and sleep. Lock it in. If we delay heart
Speaker:disease, dementia and disability long enough, many
Speaker:people will never live long enough to experience
Speaker:them. That's not cheating death, that's winning.
Speaker:At Healthspan. If you're thinking about GLP1
Speaker:drugs, work with a qualified obesity or metabolic
Speaker:health specialist. Not one of those peptide mills.
Speaker:Avoid research grade compounds sold online. That's
Speaker:lab reagent. That's not medicine. And if you want
Speaker:to go deeper into longevity medicine and
Speaker:Mediterranean eating, metabolic health and
Speaker:evidence based anti aging, join us on the
Speaker:Mediterranean Longevity Cruise. In August of 2026,
Speaker:you'll have 10 days of real food, real science,
Speaker:movement and conversations that actually matter.
Speaker:Details will be forthcoming. This was written and
Speaker:researched by me, Dr. Terry Simpson. And while I
Speaker:am a board certified physician, I am not your
Speaker:physician. Always consult your own board certified
Speaker:physician and a registered dietitian before making
Speaker:or starting any changes in medications and diets.
Speaker:All things audio are from my friends at Simpler
Speaker:Media and the pod God himself, Mr. Evo Tara. All
Speaker:right everybody, have a good week. Hey evo. At
Speaker:GLP1's the Mediterranean Diet and not drinking
Speaker:help people live longer and think clearer. Are we
Speaker:obligated to keep doing this podcast into our 90s?
Speaker:I mean, maybe. And like also, what the hell else
Speaker:we going to do, man?
