IGF-1 Expression in Skin Can Drive Age-Related Hair Loss
Aging is an accumulation of damage and dysfunction, but a quite specific collection of forms of damage and dysfunction. One can create conditions that look like premature aging, or very selective forms of premature aging of specific tissues and organs, with any number of damaging interventions, such as administration of toxins or altered expression of genes. These are not aging. Just because an intervention produces dysfunction and damage that looks like aging doesn’t necessarily mean that it has any relevance to normal aging. The details matter. It is worth remembering this point.
In today’s open access paper, the authors report on their discovery that artificially increased expression of IGF-1 in skin produces accelerated aging of hair follicles by encouraging cellular senescence. Clearing out the senescent cells or interfering in downstream targets of IGF-1 reverses this effect, restoring hair follicle function. None of this implies that IGF-1 signaling is in any way a useful target in the normal aging of hair follicles, even given that reducing IGF-1 signaling is a well studied topic when it comes to slowing aging in short-lived species, and even given evidence for increased IGF-1 signaling in skin with age. Any approach to induce greater cellular senescence in a specific cell population is going to harm its function, and there are many, many ways to go about this, few of which are relevant to cellular senescence in normal aging. To close the loop for this paper, the researchers would need to show that the treatments that work in their model of increased IGF-1 signaling also work in old mice, but they did not do that.
Targeting IGF1-Induced Cellular Senescence to Rejuvenate Hair Follicle Aging
The insulin-like growth factor-1 (IGF-1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF-1 signaling modulates organ aging remain poorly understood. In this study, we assessed age-related changes in IGF-1 expression across multiple organs in mice and identified a more prominent increase in skin IGF-1 levels with aging - a phenomenon also observed in human skin.
To explore the consequences of elevated IGF-1, we developed transgenic mice ectopically expressing human IGF-1 in the epidermis, driven by the bovine keratin 5 promoter (IGF-1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single-cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence-associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion.
Our findings indicate that excessive IGF-1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF-1 signaling via downstream mechanisms - specifically blocking acetylated p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF-1 through dietary restriction - significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.
This is a helpful review of a complicated study. Without this sort of incisive evaluation, it is hard to appreciate the limits and reasonable conclusions of any particular “scientific finding”.
More data on how low IGF-1 benefits longevity. An open access paper:
Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity
Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it. Despite its potential role in regulating lifespan, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,108 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1 :p.Ile91Leu and IGF-1 :p.Ala118Thr in our longevity cohort. Notably, a centenarian specific novel variant IGF-1:p. Ile91Leu was located at the binding interface of IGF-1–IGF-1R, whereas IGF-1 :p.Ala118Thr was significantly associated with lower circulating levels of IGF-1. We performed extended all-atom molecular dynamics simulations to evaluate the impact of Ile91Leu on stability, binding dynamics and energetics of IGF-1 bound to IGF-1R. The IGF-1 :p.Ile91Leu formed less stable interactions with IGF-1R’s critical binding pocket residues and demonstrated lower binding affinity at the extracellular binding site compared to wild-type IGF-1. Our findings suggest that IGF-1 :p.Ile91Leu and IGF-1 :p.Ala118Thr variants attenuate IGF-1R activity by impairing IGF-1 binding and diminishing the circulatory levels of IGF-1, respectively. Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.
A new IGF-1 inhibition drug has been approved by the FDA (for use in Acromegaly, where a patient has very high IGF-1 levels due to a tumor, or other defect in the pituitary gland). The price? Only $290,000 per year … @CronosTempi
Crinetics Pharmaceuticals on Thursday said the FDA greenlit its nonpeptide somatostatin receptor type 2 (SST2) agonist Palsonify (paltusotine), making a first-line once-daily oral option available for adults with acromegaly who are refractory to or unsuitable for surgery.
The product, which could offer patients freedom from frequent injections of current therapies, is expected to hit the shelves early next month — with a $290,000 yearly treatment price.
Palsonify’s clearance “marks a new era for those living with acromegaly,” said CEO Scott Struthers, adding that the “approval is the first to come from our deep pipeline of first-in-class, small molecule drugs.”
The FDA decision was supported by two Phase III pivotal trials, PATHFNDR-1 and PATHFNDR-2, which enrolled previously treated and treatment-naïve adults with acromegaly, respectively. In both studies, a significantly higher proportion of participants receiving Palsonify maintained IGF-1 levels ≤1 times the upper limit of normal compared with those on placebo, alongside significant reductions in acromegaly-associated symptoms.
Analysts at HC Wainwright last month said they were fairly confident of an approval, with a label enabling broad use across treatment-naïve patients, those switching from injectables, and those who discontinued therapy. They anticipate “treatment-naïve patients to drive the first wave of adoption post launch, with the other two groups to pick up momentum over time.”
Well, there are a number of IGF-1 inhibition drugs already on the market, it someone wanted to partake… and most of them are a little lower in price.
I suspect that there could be some moderate benefits to be derived from the use of these by healthy people for disease prevention and perhaps a little lifespan benefit. And perhaps there is some optimal pulsed dosing protocol where you get higher IGF-1 (for healing, growth, etc.) alternated with times of low IGF-1. It would need lots of experiments to find optimal dosing patterns.
From our Friendly GPT5:
Here’s a current snapshot of FDA-approved drugs used to lower IGF-1 in acromegaly (somatostatin receptor ligands, a GH-receptor antagonist, and the two oral options), with typical label dosing and list-price estimates:
Doses above are the commonly used label starting/maintenance doses—clinicians titrate to normalize IGF-1 and control symptoms, so your actual dose (and cost) may differ. Labels: Sandostatin LAR, Somatuline Depot, Signifor LAR, Somavert, Mycapssa. (FDA Access Data)
Prices shown are U.S. list prices (WAC or typical cash prices) and don’t reflect insurance, rebates, specialty-pharmacy contracts, or copay programs. (Somavert WAC from Pfizer CT disclosure; others from Drugs.com price guides; Palsonify WAC from company/press reports right after approval).
Short-acting octreotide injection is also FDA-approved for acromegaly but is typically used as a bridge/adjunct rather than long-term maintenance; not priced here. (FDA Access Data)
If you’d like, I can tailor this to target doses you’re considering (e.g., lanreotide 120 mg q4w or pegvisomant 25–30 mg/day) and recompute costs, or add payer program links that often reduce out-of-pocket expense.
Another option… buy the dog version of the drug. Loyal for Dogs is using a sister molecule to slow aging in dogs (so people can divert their dog’s prescription to themselves)…
