#123–Joan Mannick & Nir Barzilai: Rapamycin and metformin—longevity, immune enhancement, & COVID-19

KEYPOINTS

• 01

  Mannick moved into aging research at 50 to test mTOR inhibition in humans

  Around 2012, at Novartis, Joan Mannick asked to work on aging. Colleagues questioned why she'd give the drug sold to suppress the immune system in the hope of enhancing it. Her reasoning was that inhibiting mTOR had extended life in every organism tested: yeast, worms, flies and, through the NIH's Interventions Testing Program (ITP), mice. A lifespan trial in humans was impossible, so she looked for a measurable human endpoint and carefully dosed the drug to minimise side effects.

• 02

  Turning mTOR down, not off, improved immune function in older people

  Her 2014 study gave older adults a rapamycin analog (RAD001, everolimus) before a flu vaccine. The two lowest doses, 0.5 mg daily or 5 mg weekly, worked best, better than 20 mg weekly. These doses gave less mTOR inhibition. Exhausted T cells (PD-1 positive CD4 and CD8 cells, which accumulate with age) fell by about 25–30%. Attia calls the paper his '2014 Christmas gift'.

• 03

  Low intermittent doses mostly spare mTORC2

  Mannick says the low doses mainly hit mTORC1. They caused no real hyperglycaemia or high blood lipids, which are the side effects linked to mTORC2. Her newer compound, RTB101, is catalytically selective and has a 4–6 hour half-life, so once-daily dosing inhibits mTORC1 for only part of the day. She compares it most closely to 0.5 mg of everolimus daily.

• 04

  RTB101 reduced respiratory infections in phase 2

  In the first phase 2 study, six weeks of RTB101 combined with everolimus looked best. In the second, which lasted 16 weeks in a sicker population, RTB101 alone did better. In both, RTB101 reduced respiratory tract infections, and one phase 2b study showed 52% less severe disease. Mannick's interpretation is that mTOR inhibitors don't prevent infection. Instead, they produce a better immune response so symptoms are milder. Lab-confirmed infections were too few to analyse well.

• 05

  Barzilai chose metformin for strategy, not because it's the best drug

  Barzilai says rapamycin may be the better drug. Metformin was chosen for TAME (Targeting Aging with Metformin) because it is cheap, safe and generic, and has decades of data, making it a tool to establish aging as a target the FDA can accept. He cites about 30 animal studies in which metformin extended lifespan. The ITP results for metformin alone are mixed. Metformin plus rapamycin produced some of the longest-lived mice in the programme.

• 06

  The diabetic-patient paradox

  Attia highlights a frequently cited finding: people with type 2 diabetes on metformin lived longer than matched people without diabetes, despite the vascular damage diabetes causes. The guests frame metformin as acting on several interacting hallmarks of aging at once. Barzilai declines to name a single most important mechanism.

• 07

  TAME is designed to measure delay of multiple age-related diseases

  The trial is powered on 3,000 participants, and the team may expand to 3,500. It runs across 14 centres and includes ancillary studies, some needing only 250 people. Participants take 1,500 mg of extended-release metformin a day, three 500 mg tablets. That is the dose Barzilai takes himself.

• 08

  Older people's COVID risk is about comorbidity as much as immunity

  Barzilai says people aged 80 and over are about 180 times more likely to die of COVID than 20-year-olds. Attia argues that to make someone resistant you would reduce their comorbidities first, not just raise immunity by 10–20%. Both drugs might help on both fronts. Barzilai criticises ageism in leaving older people to quarantine.

• 09

  Commercial aging clocks can mislead

  Barzilai points out that clocks combine methylation with blood markers such as glucose, insulin and vitamin D. Correcting a vitamin D level of 20 with 5,000 IU a day could 'improve' biological age, even though no trial has shown vitamin D extends life. He prefers proteomics: in 1,000 people aged 65–95, hundreds of proteins changed with age. In about 500 children of centenarians, around a third of those changes were slowed.