For a long time, ageing was considered a fate nothing could be done about. Research over the past two decades is changing that. Scientists have found several cellular pathways that influence the pace of ageing, and molecules that can act on them. The best known are rapamycin, metformin and substances that replenish NAD+, especially NMN. I have been taking NMN myself for quite some time and have had a good experience with longevity drugs. That is exactly why I want you to know what is backed by evidence and where question marks remain.
How to read the numbers: Fact = a finding from research or biology
given rapamycin late in life
after mTOR inhibition
blood NAD within 60 days
Three pathways that govern ageing
Picture the cell as a construction site. mTOR is the site manager who shouts "build!" whenever food, protein and insulin are plentiful. Growth is good, but when mTOR is switched on all the time, the cell only builds and never cleans up – damaged parts pile up. AMPK is its counterweight. It switches on when energy is scarce, for example during fasting or exercise, and puts the cell into a mode of saving and repair.
The third player is the sirtuins, enzymes involved in DNA repair and in how the cell copes with stress. To work, they need the molecule NAD+. NAD+ is also essential for the mitochondria that produce energy. NAD+ levels change with age, and researchers believe their decline contributes to the ageing of metabolism and the brain. Fasting and exercise influence all three pathways naturally. Longevity drugs try to influence them in a targeted way.
Rapamycin: the strongest candidate from the lab
Rapamycin inhibits mTOR. In medicine it is used after transplants, in higher doses to suppress the immune system. Ageing research took an interest in it after 2009, when the ITP programme of the US National Institute on Aging showed that rapamycin extends the life of mice – even when they received it only in old age. Measured by the age at which 90% of the animals had died, females lived 14% and males 9% longer. The result was confirmed in three independent laboratories on genetically diverse mice.
In humans we have less so far. In a study of older volunteers, an mTOR-inhibiting drug (a relative of rapamycin) improved the response to the flu vaccine by about 20%. This is a signal that the immune system of ageing people may respond favourably to mTOR inhibition. Biohackers use rapamycin in low, intermittent doses, not daily as after a transplant. Such a regimen, however, must always be set up with a doctor.
Rapamycin and metformin are prescription drugs. They belong only in the hands of a doctor who knows your health, your blood results and your other medications. Do not dose them on your own and do not buy them from unverified sources.
Metformin: an old drug with a new role
Metformin has been prescribed for type 2 diabetes for decades. It activates AMPK, reduces glucose production in the liver and improves insulin sensitivity. Observations that diabetics on metformin fare better in some respects than expected inspired the TAME study (Targeting Aging with Metformin) led by Nir Barzilai. Its aim is to test whether metformin delays the onset of age-related diseases in humans, and at the same time to establish ageing as a target for treatment.
The picture, however, is not black and white. In the ITP programme, metformin alone did not substantially extend the life of mice, although in combination with rapamycin it did. And for people who train, the MASTERS study is important: healthy people over 65 who took 1,700 mg of metformin daily during 14 weeks of strength training gained less muscle mass than those on placebo. Metformin is therefore not a drug for everyone, and if you are actively building muscle, its use and timing need to be discussed thoroughly with a doctor.
NAD+ and NMN: fuel for the repair crew
NMN is a direct precursor of NAD+ – the cell turns it into NAD+ in a single step. Animal experiments are fairly consistent and the first human studies are promising. In a randomised study in the journal Science, NMN improved muscle insulin sensitivity over 10 weeks in postmenopausal women with prediabetes. In another study of 80 healthy middle-aged adults, doses of 300, 600 and 900 mg daily raised blood NAD levels within 60 days, most at 600 and 900 mg. Participants on NMN also improved their performance in a six-minute walking test and tolerated the supplement well.
I take NMN myself in the morning and I am satisfied with its effect. But I only added it once my foundations were in order. There is also a related precursor, NR, which works similarly. Both are available as dietary supplements, not as drugs, so the quality of the manufacturer and verified purity are important.
Foundations first: sleep, movement, strength training, a diet with enough protein and limited sugar. Only then NMN, in the morning, from a verified manufacturer with a purity analysis. Rapamycin or metformin only after talking to a doctor who knows your results and monitors you. Have blood tests done before you start and repeat them after a few months, so you can see what is really changing.
What to measure
- Fasting glucose and insulin, HbA1c – show how insulin sensitivity is developing, especially with NMN and metformin.
- Lipids – rapamycin can affect blood fats, so they need to be monitored.
- Blood count and kidney and liver function – a basic safety check with any drug.
- Vitamin B12 – its level can fall with long-term metformin use.
- Muscle mass and strength – body composition and simple strength tests tell you whether you are protecting what matters most.
- How you feel – energy, sleep, recovery and how often you get infections. Subjective feelings are not proof, but they are an important signal.
- Strong evidence Rapamycin extends the life of mice even when given in old age, repeatedly in independent laboratories; metformin is a proven and safe drug for type 2 diabetes.
- Moderate evidence NMN raises blood NAD levels and in small studies improves insulin sensitivity and physical performance; mTOR inhibition improved the vaccine response of older adults.
- Weak evidence Slowing human ageing with metformin – TAME results are still missing and metformin alone did not substantially extend mouse lifespan in the ITP.
- No evidence Extension of human lifespan by any of these substances – no such study exists yet.
Conclusion
Longevity drugs are one of the most exciting areas of modern medicine. I have had a good experience with them and I believe their time is coming. At the same time, they are an add-on, not the foundation. Rapamycin and metformin belong with a doctor, NMN with a sensible, measured approach. Start with the foundations, measure, and proceed step by step.
