#61

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.

5 Likes
#62

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”.

2 Likes
#63

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.

ć…šæ–‡ïŒš

https://www.nature.com/articles/s41598-025-94094-y

5 Likes