359 ‒ How metabolic and immune system dysfunction drive the aging process, NAD, aging clocks, & more

KEYPOINTS

• 01

  The immune system and brain may set the pace of whole-body aging

  Verdin points to work from Tony Wyss-Coray's lab finding that aging markers for the brain and immune system best predict lifespan. Both are spread throughout the body. In mice, removing the DNA-repair gene ERCC1, or causing mitochondrial dysfunction, only in immune cells speeds up aging and senescence in every organ. Whether this holds in humans is 'the million-dollar question.' Peter adds the endothelium; Verdin sees barrier function (blood vessels, skin, blood–brain barrier) as a key target.

• 02

  The oxidative-stress theory isn't dead just because antioxidants failed

  Electrons leak from the mitochondrial respiratory chain and form reactive oxygen species, and the leakage grows with age. Vitamin C and E trials failed, but Verdin says these molecules also do useful signaling: blunting them can blunt the benefits of exercise. Peter adds that the trials never had a good marker to show the antioxidants actually reduced free radicals. Martin Brand at the Buck found that blocking some production sites helped and blocking others didn't; that program was dropped.

• 03

  Fuel choice matters, and glucose is the 'dirtiest' fuel

  Verdin ranks beta-hydroxybutyrate as the cleanest fuel, then fatty acids, with glucose worst. Mice fed pure fat that never saw a carbohydrate lived longer, though Peter notes most 'high-fat' mouse diets are really high-fat, high-sugar 'donuts.' Many ITP drugs that extend life (acarbose, canagliflozin, and metformin combined with rapamycin) act on glucose. Verdin's main suspect is the insulin and IGF-1 spikes from fast-absorbing carbohydrate, and he uses CGMs to flatten them. He found a ketogenic diet socially isolating and is developing a ketone ester.

• 04

  When it comes to glucose and blood pressure, lower is usually better

  Peter cites data in non-diabetics showing all-cause mortality falls steadily as A1C goes down, with no lower limit found, so 5.0 beats 5.6 even though both count as 'normal.' Verdin's own doctor dismissed his creeping fasting glucose of 96. Both say blood pressure of 105/65 beats 115/70 if you have no symptoms. BMI is crude: Peter is 'overweight' by BMI at 11% body fat, and Verdin estimates that about 20% of overweight people are metabolically healthy, though he worries about the long term.

• 05

  Immune decline is the 'fifth horseman'

  Peter says he should have added immune health to the four horsemen in Outlive. During COVID everyone could be infected, but people over 75 had about 84-fold excess mortality. Flu and RSV follow the same pattern. Verdin explains innate immunity (fast, non-specific, no memory) and adaptive immunity (T and B cells that expand and leave memory cells). In his recollection, vaccine response drops to about 30% after 70. The two of them couldn't square that with how protective COVID vaccines seemed in the very old, and left it for the show notes.

• 06

  The thymus shrinks early, and growth hormone is a double-edged sword

  After about 50 the thymus is mostly fat, so few new naive T cells are made. Small growth hormone studies in HIV patients, and later the Fahy TRIIM trial (GH plus low-dose metformin and DHEA), suggested some thymus regrowth. Peter calls GH the only active ingredient. Verdin worries GH causes glucose intolerance, and notes that bigger dogs, driven by GH, live shorter lives, as do taller people. Peter says every patient he has seen on GH feels better, but testosterone is far better against sarcopenia.

• 07

  Rapamycin: dose and timing separate immune suppression from immune benefit

  Joan Mannick's 2014 trial (as Peter recalls it, 300+ people over 65 in four groups) found that 5 mg weekly boosted vaccine response about as well as 20 mg, with fewer side effects. Verdin took 4–6 mg weekly and got a pimple on his nose the next day, so he was clearly briefly immunosuppressed. He stopped because he noticed no benefit. He questions ITP results because lab mice live shorter than their size predicts, have high growth (mTOR) drive, eat poor chow and live sterile, sedentary lives. He would advise a 40-year-old against rapamycin.

• 08

  NAD decline seems driven by CD38, and supplements may just pour water into a leaky sink

  NAD is used by 600+ enzymes, plus sirtuins and PARPs. Eduardo Chini showed that mice without CD38 don't lose NAD with age and live about 15% longer, though Verdin suspects that isn't only because of NAD. Factors released by senescent cells (the SASP) increase CD38 in macrophages. CD38 also breaks down NMN, pushing excess nicotinamide into methylation, which drains the methyl-donor pool and raises homocysteine. Recycling is so fast that blocking it empties a cell of NAD in four to six hours.

• 09

  Epigenetic clocks aren't ready for clinical use

  Clocks can swing about five years with time of day. Matt Kaeberlein's duplicate samples disagreed within and across clocks. Blood mixes 500+ cell types: Verdin's lab found naive T cells look 20–25 years younger than memory T cells, so infections that expand memory cells fake 'accelerated aging.' His 'IntrinClock' excludes those sites and doesn't move with COVID, HIV or the GH trial. He favors DunedinPACE for tracking response to interventions. Peter notes no clock yet predicts lifespan better than chronological age.