Aging is a multifactorial process that affects skin integrity through the progressive decline of dermal fibroblast function. Dermal fibroblasts are key regulators of extracellular matrix (ECM) composition, wound healing, and tissue homeostasis. However, their dysfunction contributes to structural deterioration, chronic inflammation, and impaired regenerative capacity. Cellular senescence, a fundamental characteristic of aging, results in the buildup of senescent fibroblasts that release growth factors, matrix-degrading enzymes, and pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This study examines the impact of fibroblast senescence on dermal aging, highlighting mechanisms such as DNA damage, mitochondrial dysfunction, oxidative stress, and telomere attrition. The role of SASP-driven ECM degradation, matrix metalloproteinases (MMPs) activation, and fibroblast-keratinocyte communication breakdown are explored, demonstrating their collective contribution to skin aging. Additionally, key signaling pathways, including p16INK4a/RB, p53, NF-κB, mTOR, and TGF-β, are implicated in fibroblast senescence and chronic inflammation. Recent advancements in therapeutic strategies targeting fibroblast aging, such as senolytics, extracellular vesicle-based interventions, and metabolic reprogramming, offer promising avenues for skin rejuvenation. This review delves into the molecular and cellular dynamics of dermal fibroblast aging, emphasizing their relevance for developing novel anti-aging interventions.
Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders.The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face.
There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzled-related protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.
Dave, thanks for posting. Whenever I review papers (and I view 20 to 50 for every one I ultimately post) I focus on two things:
- what is new or interesting,
- what is something that people here might be able to use (or translate) in their daily lives to improve chances of a longer and healthier life (ideally right away, or at worse case in the not to distant future).
If you’re posting new papers it would be great if you could add some context around the papers around why you think its interesting, and how it might be implemented.
Our focus here is really on what is called “translational geroscience” - taking the science from the lab to the people for practical use.
Thanks!
Our docking results of six reported leads showed the strongest interaction against SFRP4 protein with the closest RMSD values and the most active site residues of amino acids participating in the interaction. Lead one Hesperetin was found to be the utmost potential inhibitor based on the number of interactions with amino acids in an active pocket.
Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.In
We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers.
The studies show that SFRP4, which is expressed in aged p16INK4a-positive skin fibroblasts, contributes to skin aging. In this context, the hesperetin data is relevant, since it implies that hesperetin could potentially inhibit SFRP4.
Perplexity replies:
Today this paper is mostly “pointing the way” rather than giving you ready‑to‑use clinical tools, but parts of it already map onto things in use or close to use, and overall the science is solid for a review article.
What’s usable right now?
- Good sun protection and oxidative‑stress control are directly supported: UV, ROS, and DNA damage are repeatedly shown to drive fibroblast senescence and SASP, which aligns with current advice on broad‑spectrum sunscreen, antioxidants, and avoiding chronic UV.
- Topical products that reduce MMPs and support collagen have a mechanistic rationale: compounds like rhamnose, rutinose, hesperidin, and the polysaccharide BVP‑2 lowered MMP‑1/2/9 and boosted collagen in human fibroblast models, which is exactly what many “firming” or “anti‑photoaging” formulations aim to do.
- Some plant extracts as “senomorphics” look promising in vitro: Haritaki extract, nuciferine, and a fermented rice product (maifuyin) reduced senescence markers and SASP cytokines (IL‑6, IL‑8, CXCL2, MMP‑1) in stressed human dermal fibroblasts, suggesting a plausible role as active cosmetic ingredients rather than magic cures.
- Regenerative approaches under active study: mesenchymal stromal cell–derived extracellular vesicles (EVs) from carefully selected donors improved fibroblast survival, reduced ROS and SASP, and promoted a pro‑regenerative fibroblast subtype in preclinical models, which fits ongoing work on EV‑based skin rejuvenation and wound‑healing products.
In other words, the paper gives mechanistic backing for: “protect from UV/oxidative damage, preserve collagen, and gently modulate senescent cells and inflammation,” which is exactly the direction high‑end dermatology and cosmeceuticals are moving.
Does it “hold water”?
- As a review, it is built on many in vitro (cell culture) and animal studies; that is standard for geroscience and means the mechanistic story is strong but not yet proven in large human trials for every proposed intervention.
- The core ideas—fibroblast senescence, SASP‑driven MMP upregulation, ECM degradation, and links to inflammaging and cancer risk—are supported by multiple independent groups, single‑cell RNA‑seq in human skin, and histology in young vs old donors.
- The authors correctly note caveats: senescent cells are heterogeneous (“senescent drift”), MSC‑EVs can be harmful if sourced from aged/stressed donors, and broad senolytic or EV therapies could backfire without careful design and testing.
- Where it becomes speculative is when moving from “this plant extract reduced IL‑6 and SA‑β‑gal in fibroblasts” to “this could be a therapy for human skin aging”; those leaps need controlled clinical trials, which the paper does not yet provide.
So: the mechanisms and direction of travel are trustworthy, and they reinforce current best practices and next‑gen anti‑aging strategies, but most of the specific “new” agents (senolytics/senomorphics, EV therapies, CRAT‑targeting, precise chemokine blockade) are still at the preclinical or early‑translation stage rather than proven, off‑the‑shelf treatments.
Hesperidin dissolved in Transcutol can be added to CeraVe cream or mixed with HA serum (and delivered by electroporation may be?).