Hi Reader,

The FDA just approved the first mitochondrial drug in history. And new research explains why your NAD+ supplements might not be working.

Both stories point to the same thing: the longevity industry has been thinking about mitochondrial health wrong.

💊 Why Your $100/Month NAD+ Supplement Might Be Useless

NAD+ boosters, mitophagy enhancers, and most mitochondrial supplements work for some people, but do absolutely nothing for others.

Before we dig into why, let's start with some basics.

Your mitochondria are important in longevity because their job is to turn food into energy (ATP). When they work well, you feel energized, recover fast, and maintain muscle.

The problem: They start failing in your 40s and 50s. Less energy production, more cellular damage. This is why you're more tired at 50 than you were at 25, even if you sleep the same amount and exercise more.

The supplement industry's solutions:​
Boost NAD+ which helps mitochondria function (and declines with age) → mitochondria make more energy → you feel better.

Boost the recycling system (mitophagy) → renovate existing mitochondria → you feel better.

The reality:​
This works great... unless your mitochondrial structure is already compromised. Then you're just pouring expensive fuel into a broken engine.

The Mitochondrial Breakthrough: Structure Matters as Much as Fuel

It turns out your mitochondria have specialized "construction zones" on their surface that build structural proteins on-site. These zones—called MATOs—keep the mitochondrial structure intact.

The problem: These zones disappear as you age. And when they're gone, your mitochondria physically collapse.

In lab animals (C. elegans worms):

• When MATOs stick around during aging → 30-50% lifespan extension, better stress resistance
• When MATOs disappear (the normal aging pattern) → rapid mitochondrial deterioration, 20-30% drop in ATP

The catch: This is very early science. While we are starting to see drugs supporting mitochondrial structure (see below), they're not working on this exact mechanism yet.

​

So Do NAD+ Boosters and Urolithin A Still Work?

Short answer: Yes, but with important caveats.

​Urolithin A (Mitopure):​
Still has the strongest human evidence. Triggers mitophagy—the cleanup of damaged mitochondria. Multiple studies showing improvements in muscle function and endurance.

Best for: People with measurable fatigue, muscle weakness, or declining physical function. (FWIW I haven't *felt* much when I've tried it myself! But...I'm still working through a long supply of it so will keep you posted.)

NAD+ boosters (NMN, NR):​
Some people see clear benefits in energy, cognition, and vascular health. Others see nothing.

The key factor: timing and baseline status. If you're 45 with relatively healthy mitochondria, NAD+ boosting can help preserve function. If you're 70 with significant structural damage, boosting fuel alone won't work—you need structural interventions too.

Big money is already moving: NRG Therapeutics just raised $67M for mitochondrial therapies in neurodegeneration. Cellvie is developing mitochondrial transplantation tech.

⚡ Energy Boost: What You Should Do Now for Mitochondrial Health

The non-negotiable foundation (works for everyone):

• 7-9 hours consistent sleep
• 0.8-1g protein per pound bodyweight daily depending on activity
• Resistance training 2-3x/week
• Zone 2 cardio, HIIT 2-3x/week
• Manage blood sugar (prioritize protein + fiber, avoid constant snacking)
• Heat/cold exposure (sauna, cold plunge when accessible)

Note: We don't know if these preserve MATOs specifically, but they support mitochondrial health through other proven mechanisms.

Interventions that have human evidence:

​Urolithin A (Mitopure): The best evidence for any mitochondrial supplement. Triggers mitophagy—cleanup of damaged mitochondria. Multiple human studies showing real improvements in muscle function.

Best for: People over 50 with measurable fatigue or muscle weakness.

NAD+ boosters: Work for some people, do nothing for others.

The pattern: They seem to work better if you're 35-50 and starting from relatively healthy mitochondria (preservation mode). Less effective if you're older with more structural damage (repair mode).

Try it for 3 months. Track objective measures (energy, recovery, strength). If nothing changes, stop wasting money.

Don't bother with:

• Random mitochondrial supplements without human studies
• Any intervention as a substitute for the basics
• Continuing something that clearly isn't working for you—you should feel the difference quite obviously

​

A Mitochondria Peptide Drug Just Got FDA Approved

On September 19, 2025, the FDA approved something that's never existed before: a drug that directly repairs mitochondrial structure.

The drug: Elamipretide (brand name: Forzinity)

Better known as SS-31 in biohacker circles (more on this later)

What it does: Stabilizes cardiolipin—a critical fat molecule in your inner mitochondrial membrane. When cardiolipin breaks down, your mitochondria can't maintain their structure or produce energy. This drug fixes that.

Who it's for: Barth syndrome—a rare genetic disease that causes severe muscle weakness and heart problems in young males.

The Results That Matter

In the TAZPOWER trial:

• Patients saw significant improvements in how far they could walk (6-minute walk test)
• Knee muscle strength improved substantially (some subgroups up to 45%)
• About 80% of patients maintained benefits over 8+ years
• No new safety problems after 8 years of continuous use

This is huge for three reasons:

1. It proves the concept works in humans—not just in mice or cells in a dish, but in actual people over years
2. It validates an entire approach—targeting mitochondrial structure directly
3. It opens the door for 1,000+ other conditions—primary mitochondrial diseases affect about 1 in 5,000 people worldwide

What This Drug Is NOT

❌ It's not available as a supplement
❌ No solid evidence for other indications (chronic fatigue syndrome, long-COVID)
❌ It's prescription-only for Barth syndrome specifically

Danger zone: You can find "SS-31" (elamipretide's research code) sold online as "research peptides" by vendors like Peptide Sciences. These are unregulated chemicals with no FDA oversight. Even if they claim high purity, you're taking a huge risk.

Why Biohackers Love SS-31

Even given all the risks, people have been self-experimenting with SS-31 in the gray peptide market for years.

If you have chronic fatigue, post-viral syndrome, or age-related energy decline, your options are, unfortunately, quite limited. Folks who are desperate have been leaning on animal data suggesting improved exercise tolerance, reduced inflammation, and muscle function.

What responsible use would look like (if prescribed off-label):

• Start low: 250 mcg under medical supervision
• Track objective biomarkers: Inflammation markers (hs-CRP, GlycA), mitochondrial function tests if available
• Monitor for more serious side effects beyond injection site reactions
• Cycle rather than continuous use (1-3 months at a time is typical)
• Source from legitimate compounding pharmacies only, never research chemical sites

The FDA approval validates that this mechanism works. It doesn't make unregulated self-experimentation safe.

But it does mean more physicians may be willing to prescribe it off-label for mitochondrial dysfunction, which could provide a safer path than buying peptides for research-use-only sources.

The Peptide Future Is Coming Fast

AI is changing the game: A new system called PepThink-R1 uses AI to design peptides that are more stable and more likely to work as drugs. It's the first system that can explain its reasoning step-by-step.

What this means: Experts predict over 50 new peptide drug candidates by 2030 for metabolic disease, neurodegeneration, and aging.

Other Peptides People Keep Asking About

MOTS-c and Humanin: Great results in mice (longer life, better metabolism). Although there's no strong human trial data—just observational studies showing low levels correlate with disease—I know of several doctors who have recommended MOTS-c. That being said, I would caution before jumping on these less proven peptides.

⚡ This Week's Longevity Speed Round

Midi Health ($50M Series C): Scaling women's preventive longevity care. Proves this can work outside $10K/year concierge clinics.

LinkGevity's Link-001: First drug targeting calcium-induced cell death in aging. Human trials starting.

Women live 5.8 years longer than men—and the science explains why men need to stop being stubborn: NPR just covered a massive study of 528 mammal species showing the "caretaking parent" lives longer. In these species, males sacrifice longevity for mating success (bigger bodies, taking risks, competition). The fix? Men who mimick women's health behaviors—regular doctor visits, better diet, focusing on prevention—narrow the gap.

Your "one glass of wine" habit might be destroying your brain: Massive new study combining observational and genetic data found NO safe level of alcohol for dementia risk. The old "light drinking protects the brain" belief? Dead. Dementia risk rises in direct proportion to consumption. Sorry.

Living with purpose cuts dementia risk by 28%: UC Davis tracked 13,000+ adults for 15 years. People with higher sense of purpose were 28% less likely to develop cognitive impairment. Not supplements. Not biohacks. Purpose. Figure out what you're living for.

🚀 Where You Can Find Me

I've got some cool events coming up where we can geek out about longevity in person:

🧘 Nervous System Reset – Oct 6, NYC. Doing something different! Join my fireside chat at a beautiful wellness space followed by a sound bath — perfect for a reset.

🎤 Ageless Evolution Summit – Oct 10, Silicon Valley. I'll be speaking First Principles Longevity in Mountain View. Come say hi! Use code DRLIN30 for 30% off your ticket.

⭐ DOC Longevity – Oct 12-14, Napa Valley. I'll be a DOC Fellow this year!

🌐 HLTH USA – Longevity Session – Oct 19–22, Las Vegas. Panel: “Death Becomes Optional.” I'm on stage with the CEO of Nestle Health Science and CSO of Niagen Biosciences. Use code 25HLTH_SPKG_250 for $250 off

💯 Longevity Global Summit – Dec 9-10, Marin County, CA. I'll be speaking with fellow longevity leaders from Buck Institute, Stanford, and more at the longevity research institute itself!

Finally, NeuroAgeTx is offering the most comprehensive and science-backed brain aging package to The Longevity Letter readers at up to 61% off (affiliate link here).

The Bottom Line

1. We finally know why NAD+ works inconsistently: It's not about fuel—it's about structure. If your mitochondrial architecture is compromised, boosting fuel won't help. This explains everything.

2. The FDA validated structural repair works in humans: Not just in mice, but in actual people over 8+ years. This opens the door for everyone who's been told "your fatigue is just aging" when something structural is actually broken.

What you should do:

Master the basics first: sleep, protein, resistance training, metabolic health. These work for everyone.

If you're taking NAD+ or other mitochondrial supplements and feeling nothing after 3 months, stop. Save your money or spend it on a trainer who'll help you do the fundamentals right.

If you're considering off-label peptides: talk to a longevity physician who can prescribe from legitimate sources and monitor you properly. Track biomarkers, not (just) feelings.

The future isn't "everyone take this supplement." It's "fix your specific bottleneck with the right tool, at the right time."

Hillary Lin, MD

Co-Founder & CEO

​Care Core​

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Follow me for more longevity insights: YouTube | LinkedIn | Instagram | TikTok​

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