Regrowing the Thymus: Greg Fahy on Immune Rejuvenation and the TRIIM Trials
Greg Fahy explains why the shrinking thymus may be one of the most consequential parts of aging, and how a combination of growth hormone, DHEA and metformin appeared to regrow it in his human trials. He walks Matt Kaeberlein through the imaging, the T-cell markers, the surprising fitness and blood-pressure changes, and the open questions the work still has to answer.
Overview
Greg Fahy traces the origin of TRIIM back to a 1990 rat study in which old animals regrew a fully functional thymus after receiving growth-hormone-producing pituitary implants - a result nobody followed up on. Frustrated by the silence, he tested the idea on himself, and discovered that adding DHEA cancelled the insulin rise growth hormone caused; metformin was later added as a third component.
He describes thymic involution as a genuine loss of cells replaced by fat, beginning around puberty and continuing for life, with only a small functional remnant left in older adults. A 2023 cardiac-surgery cohort showed that removing even that remnant tripled four-year mortality and multiplied cancer recurrence risk. In his trials, MRI showed fat being replaced by functional thymic tissue, while naive CD4 and CD8 T cells rose and recent thymic emigrants increased by 60%.
Unexpectedly, the volunteers also showed large functional changes - a 24% rise in VO2 max, muscle measures consistent with a decade of reversal, and drops in pulse and diastolic blood pressure - without being asked to change their lifestyle. Fahy and Kaeberlein then debate epigenetic clocks, their error bars and circadian swings, and whether functional improvement counts as reversing aging. The conversation closes on funding, cost, and the next protocol version aimed at raising IGF-1 with far less growth hormone.
Key quotes
5I tried it on myself, because nobody else was going to do anything. I didn't have a laboratory. I just had myself.
Because if you don't have a thymus, you die.
Within four years, your risk of dying is increased by a factor of three.
Between the ages of 62 and 78 you lose 98% of your ability to recognize foreign antigens.
We saw improvements in VO2 max that are ridiculous - like a 24% improvement.
Key ideas
9A rat study nobody followed up
In 1990 Fahy read that old rats regrew a normal thymus after implants of growth-hormone-producing pituitary cells. Treated at 16 months, their thymus looked and functioned like that of a three-month-old animal. When the field ignored the result, he decided to pursue it himself.
The insulin problem with growth hormone
Growth hormone raises insulin through several routes, including lipolysis that floods the blood with fatty acids and blunts insulin sensitivity. Fahy found DHEA largely cancelled that rise, and later added metformin because DHEA alone lost strength with age.
Involution means losing cells, not shrinking them
Thymic involution is the replacement of functional tissue with fat, accelerating around puberty and continuing throughout life. A small amount of working thymic tissue persists even at very advanced ages.
What happens when the remnant is removed
In a cohort of adults whose thymus was discarded during open-heart surgery, four-year mortality tripled, functional and cognitive decline doubled, and cancer recurrence rose roughly fourfold. The remnant is small but far from irrelevant.
The thymus has two jobs
It manufactures T cells in the cortex and screens out self-reactive ones in the medulla. As both functions weaken, you get fewer defenders and more autoimmunity - a possible explanation for the chronic low-grade inflammation of aging.
The immune cliff in late life
The T-cell receptor repertoire at 60 is similar to that at 20, which masked the problem for decades. Then replacement falls behind loss, and recognition of foreign antigens drops by roughly two orders of magnitude between 62 and 78.
How regrowth was measured
MRI cross-sections showed fat giving way to functional tissue. Naive CD4 T cells rose about 13% and CD8 about 20%, recent thymic emigrants rose 60%, and PD-1-expressing senescent CD8 cells declined.
Function followed structure
Volunteers were told not to change their lifestyle, yet showed a 24% VO2 max increase, muscle measures consistent with a decade of reversal, pulse falling from 70 to 60, and diastolic pressure from 85 to 68 over a year.
The growth hormone paradox
Dwarf and knockout models live longer, but Fahy argues they are developmentally rewired animals kept in clean, temperature-controlled cages. Kaeberlein pushes back with small dogs, which live longer without obvious immune deficits - the disagreement stays open.
Practical takeaways
7- 1
The evidence base is early 12:30
The story starts with a self-experiment and continues through small, unblinded trials. Interesting as science, but not something to treat as settled or as personal guidance.
- 2
Fasting insulin and glucose were the safety dial 24:00
The whole protocol was built around keeping insulin from drifting up. Fasting values, taken after a consistent evening meal, remain a simple metabolic marker anyone can follow with their clinician.
- 3
Small tissue, large consequences 33:00
Even a modest amount of functional thymus appears to carry real weight for immune surveillance later in life. Worth knowing about if thymus removal ever comes up in a surgical conversation.
- 4
Naive T cells describe immune age 47:00
Naive CD4/CD8 counts and recent thymic emigrants say more about immune aging than total white cell counts. They are the numbers Fahy watches most closely.
- 5
VO2 max is the marker to track 1:06:00
Both speakers call it among the strongest single predictors of mortality. It can be measured and improved through ordinary training, with no protocol involved.
- 6
Read epigenetic clocks as trend lines 1:10:00
Error bars are real, results even shift across the day, and a single expensive reading tells you little. Repeated measurements and the direction of travel are what matter.
- 7
Be careful extrapolating from castration studies 1:28:00
The link between sex hormones and thymic decline rests mostly on animal work. Fahy is explicit that human evidence for hormone therapy harming the thymus is not there.
Topics & chapters
16How TRIIM began
Fahy recalls the 1990 rat result and his 1991 editorial calling for follow-up. Nothing happened, so he took the question on himself.
Growth hormone's mixed reputation
The Rudman study, the anti-aging clinics, bodybuilder abuse and the metabolic side effects that gave growth hormone its bad name.
Why insulin rises - and how DHEA helps
Lipolysis, lipotoxicity and PI3K-AKT signalling. Fahy's own week-by-week experiment showing DHEA restored his insulin to normal.
Adding metformin as the third piece
As he aged, DHEA alone no longer held insulin down. Metformin joined the protocol, with fasting insulin and glucose as the monitoring points.
What thymic involution actually is
A genuine loss of thymic cells replaced by fat, triggered around puberty. Some stem and epithelial cells survive, which is what makes regrowth conceivable.
Imaging the thymus
MRI cross-sections let them separate fatty from functional tissue and compare each person to their own baseline.
Why the thymus matters
The heart-surgery cohort in which the remaining thymus was sometimes discarded, and the sharp increases in mortality, functional decline and cancer recurrence that followed.
T cells, autoimmunity and inflammaging
The thymus both produces T cells and screens out self-reactive ones. Fahy argues its decline helps explain the chronic inflammation of aging.
The markers of thymic output
Naive CD4 and CD8 cells, and recent thymic emigrants identified by the DNA circles they still carry.
Rapamycin and the thymus
Fahy describes rapamycin as blocking T-cell maturation, complicating its role here. Kaeberlein questions dose, duration and whether the effect is cytostatic rather than toxic.
Senescent T cells and the trial design
PD-1-expressing CD8 cells fell as new T cells appeared. The trials use each person as their own control, with a crossover design now underway.
Exercise capacity and cardiovascular changes
VO2 max, muscle strength, pulse and diastolic blood pressure all moved substantially over a year without instructed lifestyle change.
Epigenetic clocks - promise and error bars
A long exchange on what the clocks measure, direct-to-consumer variability, and the finding that biological age readings shift within a single day.
What comes next: TRIIM-XD, IGF-1 and cost
The next protocol aims to optimise the interaction of the three medications, raise IGF-1 with far less growth hormone, and bring the price down.
Growth hormone versus longevity dogma
Knockout mice, Laron dwarfs and small dogs. Fahy argues developmental models cannot be applied to adults; Kaeberlein pushes back.
Sex hormones, pregnancy and repeat cycles
Castration regrows the thymus in animals, pregnancy shrinks it temporarily, and Fahy hopes regeneration could be repeated over a lifetime.