The Twin Engines of Longevity

Happy Friday!

I just dropped a brand-new video on SGLT2s and GLP-1s.

I discuss how they work, why I use them, and why I think this combo is the most powerful clinical longevity lever we have today.

After a community member put SGLT2s on my radar a couple of years ago, I dove into the literature, tried them myself, and started tracking my own longevity biomarkers.

I’m not saying they are a “miracle drug,” but I am saying the data is pretty remarkable.

In today’s email, I distill the latest research on lifespan, healthspan, and GLP-1 combo therapy so you can see exactly where the evidence is strongest and how it aligns with what I’m seeing in the wild.

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Lifespan

The cleanest lifespan data come from the NIH Interventions Testing Program.

In genetically heterogeneous male mice, canagliflozin extended median lifespan by approximately 14% across three test sites.

In the mice, both sexes improved glucose handling, and females dropped fat mass.

Mechanistically, investigators think blunting glucose peaks may explain the increase in lifespan.

Fewer post-prandial spikes means less glyco-oxidative stress, resulting in slower multi-organ decline.

Daily glycemic variability accelerates aging, and SGLT2s smooth its fluctuations. 

Human Outcomes

Humans don’t have randomized “live longer” trials, but we do have hard endpoints.

The EMPA-REG OUTCOME trial first showed a 32% reduction in all-cause mortality with empagliflozin in high-risk type 2 diabetes.

Since then, meta-analyses covering tens of thousands of patients have consistently shown lower cardiovascular death and heart-failure hospitalizations across ejection-fraction phenotypes, and benefits that extend into non-diabetic heart failure and CKD indications.

2025 analyses now show SGLT2 use after acute coronary events is associated with significantly lower all-cause mortality, with larger effects in those who also have type 2 diabetes.

While we can’t claim human lifespan extension, we can say SGLT2s reduce the events most likely to end life early. 

Why They Work

SGLT2s shed glucose in urine, subtly lowering glucose and insulin while nudging glucagon up.

The cell reads this as a mild energy deficit.

AMPK goes up, mTOR tones down, fatty-acid oxidation ramps, ketones rise, and FGF21 increases (remeber the sugar diet).

Functionally, it’s a “fasted-like” state with ongoing caloric intake, which is why you often see fat loss without the usual metabolic slowdown.

In the heart, there’s a well-documented fuel shift toward ketones and fatty acids.

Clinically, that maps to fewer heart failure admissions and better kidney outcomes, even when glucose control alone would predict far less.

SGLT2s reprogram metabolism toward efficiency and repair while improving major biological systems. 

Senescence and Inflammation

One of the most exciting 2024 papers in Nature Aging showed that short courses of canagliflozin reduced senescent cell burden in diet-induced obese mice, dampened the SASP (inflammatory secretome), and improved adipose inflammation.

A commentary the same year proposed SGLT2s as senotherapeutics, potentially enhancing immune clearance of old cells via PD-L1 downregulation.

Fewer senescent cells mean less chronic inflammation, better tissue function, and more resilient mitochondria.

It’s plausible that cardiometabolic risk falls because the cellular aging program slows down.

1 + 1 = 3

GLP-1s primarily cut appetite, improve glycemic control, and reduce atherosclerotic events.

SGLT2s help by increasing the amount of calories you burn, improving heart and kidney health, and reducing the risk of heart failure.

Put them together, and you cover both fronts.

A 2025 systematic review shows combo therapy delivers superior cardiovascular, weight, and HbA1c outcomes vs. either class alone, with the main trade-off being more GLP-1-like GI effects (nausea, constipation, diarrhea, etc).

Large real-world analyses have shown that combining treatments can lead to fewer deaths and hospital visits in people with metabolic-associated fatty liver disease.

Additionally, studies after acute coronary syndrome (ACS) suggest that these treatments work even better together, providing extra benefits in reducing death rates and preventing recurrent heart attacks.

In practice, I’ve seen two pragmatic wins.

You can often keep the GLP-1 dose lower (fewer side effects), and your progress keeps improving month over month rather than stalling. 

In Practice

When people add an SGLT2, I see hs-CRP, fasting insulin, triglycerides, and waistline move in the right direction even before big diet changes.

Add a micro-dose of a GLP-1, and the satiety “ceiling” drops, making adherence easier.

My own labs have steadily improved on this stack, and the pattern has been repeatable in people who previously plateaued on lifestyle alone.

I’ve seen striking cases in “tough metabolizers” and even in my own family.

My father-in-law saw improvements in stamina, blood pressure, and labs on Jardiance, and the momentum kept building after layering in low-dose retatrutide.

None of this replaces nutrition, lifting, and sleep.

But when you align hormones and metabolic health (think testosterone optimization plus SGLT2 plus GLP-1), the compound effect on healthspan becomes obvious in the mirror and on paper.

Final Thoughts

We still need to see longer safety and aging studies in people without diabetes.

However, data from 2025 shows that SGLT2 inhibitors are promising for heart failure, chronic kidney disease, and post-acute coronary syndrome risks, regardless of diabetes status.

Research on combination therapies continues to grow.

Practically speaking, start with the basics like good nutrition, regular exercise, walking, and quality sleep.

If you have insulin resistance, a risk of heart failure or kidney problems, or difficulty losing fat, you might want to think about using SGLT2 inhibitors.

If you’re already using a GLP-1, think about adding an SGLT2 to reduce the GLP-1 dose while boosting heart and kidney protection.

I believe that in five years, we’ll look back and see SGLT2 inhibitors as one of the first widely adopted therapies that truly enhanced population healthspan.

For now, these are the most practical and powerful tools that many people haven't yet explored but might want to consider adding to their stack.

Best,

Hunter Williams

Further reading (studies & reviews)

• Canagliflozin extends lifespan in male mice (ITP): Miller et al., JCI Insight 2020.

• Nature Aging: SGLT2 inhibition reduces senescence / alleviates pathological aging: Katsuumi et al., 2024.

• Commentary on SGLT2s as senotherapeutics: Le Bras, Lab Animal 2024.

• EMPA-REG OUTCOME (mortality ↓ 32% with empagliflozin): Zinman et al., NEJM 2015.

• Heart failure meta-analysis across phenotypes: ACC Journal Scan (meta of RCTs), 2022.

• Post-MI all-cause mortality reduction (2025 meta-analysis): Maremmani et al., Cardiovascular Diabetology 2025.

• Combo therapy SGLT2 + GLP-1 improves CV/renal outcomes (systematic review): Mousavi et al., Diabetology & Metabolic Syndrome 2025.

• Dual-therapy cardiorenal outcomes (systematic review): Shokravi et al., 2025.

• Combination in MASLD (retrospective cohort, better outcomes vs SGLT2 alone): Wu et al., Nature Communications 2025.