Skin health and biological aging

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

Article  PubMed  PubMed Central  Google Scholar 

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

Article  PubMed  Google Scholar 

Krutmann, J. Pollution and skin: from epidemiological and mechanistic studies to clinical implications. J. Dermatol. Sci. 76, 163–168 (2014).

Article  PubMed  Google Scholar 

Fisher, G. J. Pathophysiology of premature skin aging induced by ultraviolet light. N. Engl. J. Med. 337, 1419–1429 (1997).

Article  CAS  PubMed  Google Scholar 

Gruber, F., Kremslehner, C., Eckhart, L. & Tschachler, E. Cell aging and cellular senescence in skin aging—recent advances in fibroblast and keratinocyte biology. Exp. Gerontol. 130, 110780 (2020).

Article  CAS  PubMed  Google Scholar 

Hughes, B. K. & Bishop, C. L. Current understanding of the role of senescent melanocytes in skin ageing. Biomedicines 10, 3111 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, J., Yu, H., Man, M. & Hu, L. Aging in the dermis: fibroblast senescence and its significance. Aging Cell 23, e14054 (2024).

Article  CAS  PubMed  Google Scholar 

He, X., Gao, X. & Xie, W. Research progress in skin aging and immunity. Int. J. Mol. Sci. 25, 4101 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lyons, C. E., Razzoli, M. & Bartolomucci, A. The impact of life stress on hallmarks of aging and accelerated senescence: connections in sickness and in health. Neurosci. Biobehav. Rev. 153, 105359 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Saini, N. UV-exposure, endogenous DNA damage, and DNA replication errors shape the spectra of genome changes in human skin. PLoS Genet. 17, e1009302 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Petr, M. A., Tulika, T., Carmona-Marin, L. M. & Scheibye-Knudsen, M. Protecting the aging genome. Trends Cell Biol. 30, 117–132 (2020).

Article  CAS  PubMed  Google Scholar 

Agrawal, R., Hu, A. & Bollag, W. B. The skin and inflamm-aging. Biology 12, 1396 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schumacher, B., Pothof, J., Vijg, J. & Hoeijmakers, J. H. J. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jin, S. Hallmarks of skin aging: update. Aging Dis. 14, 2167–2176 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Hernando, B. The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin. Ann. Oncol. 32, 412–421 (2021).

Article  CAS  PubMed  Google Scholar 

Wang, A. S. & Dreesen, O. Biomarkers of cellular senescence and skin aging. Front. Genet. 9, 247 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Bauwens, E. Senescence induced by UVB in keratinocytes impairs amino acids balance. J. Invest. Dermatol. 143, 554–565 (2023).

Article  CAS  PubMed  Google Scholar 

Mouret, S., Forestier, A. & Douki, T. The specificity of UVA-induced DNA damage in human melanocytes. Photochem. Photobiol. Sci. 11, 155–162 (2012).

Article  CAS  PubMed  Google Scholar 

Inomata, K. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009).

Article  CAS  PubMed  Google Scholar 

Sotiropoulou, P. A. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat. Cell Biol. 12, 572–582 (2010).

Article  CAS  PubMed  Google Scholar 

Plikus, M. V. Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling. Proc. Natl Acad. Sci. USA 110, 2106–2115 (2013).

Article  Google Scholar 

Janich, P. Human epidermal stem cell function is regulated by circadian oscillations. Cell Stem Cell 13, 745–753 (2013).

Article  CAS  PubMed  Google Scholar 

Solanas, G. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692 (2017).

Article  CAS  PubMed  Google Scholar 

Mortimer, T. The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis. Cell Stem Cell 31, 834–849 (2024).

Article  CAS  PubMed  Google Scholar 

Taub, A. F. & Pham, K. Stem cells in dermatology and anti-aging care of the skin. Facial Plast. Surg. Clin. North Am. 26, 425–437 (2018).

Article  PubMed  Google Scholar 

Ge, Y. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Matsumura, H. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

Article  PubMed  Google Scholar 

Langton, A. K., Halai, P., Griffiths, C. E. M., Sherratt, M. J. & Watson, R. E. B. The impact of intrinsic ageing on the protein composition of the dermal-epidermal junction. Mech. Ageing Dev. 156, 14–16 (2016).

Article  CAS  PubMed  Google Scholar 

Vilas, J. M. Adult Sox2⁺ stem cell exhaustion in mice results in cellular senescence and premature aging. Aging Cell 17, e12834 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Yue, T. & Li, D. Senescent stem cell dysfunction and age-related diseases. Stem Cells Dev. 32, 581–591 (2023).

Article  CAS  PubMed  Google Scholar 

Flores, I., Cayuela, M. L. & Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253–1256 (2005).

Article  CAS  PubMed  Google Scholar 

Siegl-Cachedenier, I., Flores, I., Klatt, P. & Blasco, M. A. Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. J. Cell Biol. 179, 277–290 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Blackburn, E. H. & Epel, E. S. Too toxic to ignore. Nature 490, 169–171 (2012).

Article  CAS  PubMed  Google Scholar 

Li, J. Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1. J. Invest. Dermatol. 132, 2681–2690 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat. Rev. Mol. Cell Biol. 10, 207–217 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pilkington, S. M., Bulfone-Paus, S., Griffiths, C. E. M. & Watson, R. E. B. Inflammaging and the skin. J. Invest. Dermatol. 141, 1087–1095 (2021).

Article  CAS  PubMed  Google Scholar 

Lee, Y. I., Choi, S., Roh, W. S., Lee, J. H. & Kim, T. -G. Cellular senescence and inflammaging in the skin microenvironment. Int. J. Mol. Sci. 22, 3849 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Baechle, J. J. Chronic inflammation and the hallmarks of aging. Mol. Metab. 74, 101755 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Franceschi, C. & Campisi, J. Chronic Inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69, 4–9 (2014).

Article  Google Scholar 

Barker, J. N. Modulation of keratinocyte-derived interleukin-8 which is chemotactic for neutrophils and T lymphocytes. Am. J. Pathol. 139, 869–876 (1991).

CAS  PubMed  PubMed Central  Google Scholar 

Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

Article  CAS  PubMed  Google Scholar 

Rhie, G. et al. Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J. Invest. Dermatol. 117, 1212–1217 (2001).

Article  CAS  PubMed  Google Scholar 

Rinnerthaler, M., Bischof, J., Streubel, M. K., Trost, A. & Richter, K. Oxidative stress in aging human skin. Biomolecules 5, 545–589 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rabe, J. H., Mamelak, A. J., McElgunn, P. J. S., Morison, W. L. & Sauder, D. N. Photoaging: mechanisms and repair. J. Am. Acad. Dermatol. 55, 1–19 (2006).

Article  PubMed  Google Scholar 

Qian, H. Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging: current evidence and future perspectives. Front. Bioeng. Biotechnol. 10, 1082403 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Hussain, M. Skin abnormalities in disorders with DNA repair defects, premature aging, and mitochondrial dysfunction. J. Invest. Dermatol. 141, 968–975 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, H. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).

Article  CAS  PubMed  Google Scholar 

Lyu, Y. & Ge, Y. Toward elucidating epigenetic and metabolic regulation of stem cell lineage plasticity in skin aging. Front. Cell Dev. Biol. 10, 903904 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Orioli, D. & Dellambra, E. Epigenetic regulation of skin cells in natural aging and premature aging diseases. Cells 7, 268 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vijg, J. & Dong, X. Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell 182, 12–23 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Martincorena, I. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Katsyuba, E., Romani, M., Hofer, D. & Auwerx, J. NAD⁺ homeostasis in health and disease. Nat. Metab. 2, 9–31 (2020).

Article  CAS  PubMed  Google Scholar 

Oblong, J. E. The evolving role of the NAD⁺/nicotinamide metabolome in skin homeostasis, cellular bioenergetics, and aging. DNA Repair 23, 59–63 (2014).

Article  CAS  PubMed  Google Scholar 

Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).

Article  CAS  PubMed  Google Scholar 

Li, T. Y. The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. Nat. Aging 1, 165–178 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 20, 421–435 (2019).

Article  CAS  PubMed  Google Scholar 

Victorelli, S. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature 622, 627–636 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gorgoulis, V. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

Article  CAS  PubMed  Google Scholar 

Low, E. How good is the evidence that cellular senescence causes skin ageing?. Ageing Res. Rev. 71, 101456 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wallis, R., Mizen, H. & Bishop, C. L. The bright and dark side of extracellular vesicles in the senescence-associated secretory phenotype. Mech. Ageing Dev. 189, 111263 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Victorelli, S. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 38, e101982 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pereira, B. I. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8⁺ T cell inhibition. Nat. Commun. 10, 2387 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Deruy, E. Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion. Cell Death Dis. 5, 1577 (2014).

Article  Google Scholar 

Kim, H. S., Park, S. -Y., Moon, S. H., Lee, J. D. & Kim, S. Autophagy in human skin fibroblasts: impact of age. Int. J. Mol. Sci. 19, 2254 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Fitsiou, E., Pulido, T., Campisi, J., Alimirah, F. & Demaria, M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. J. Invest. Dermatol. 141, 1119–1126 (2020).

Article  PubMed  Google Scholar 

Song, S. B., Shim, W. & Hwang, E. S. Lipofuscin granule accumulation requires autophagy activation. Mol. Cells 46, 486–495 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi, Y. J. The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging. Oncotarget 7, 52685–52694 (2016).

Article  PubMed  PubMed Central  Google Scholar 

Amorim, J. A. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat. Rev. Endocrinol. 18, 243–258 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Böhm, M. et al. Endocrine controls of skin aging. Endocr. Rev. https://doi.org/10.1210/endrev/bnae034 (2025).

Slominski, A. T. Neuroendocrine signaling in the skin with a special focus on the epidermal neuropeptides. Am. J. Physiol. 323, 1757–1776 (2022).

Article  Google Scholar 

Ghosh, T. S., Shanahan, F. & O’Toole, P. W. The gut microbiome as a modulator of healthy ageing. Nat. Rev. Gastroenterol. Hepatol. 19, 565–584 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Zhou, Y., Hu, G. & Wang, M. C. Host and microbiota metabolic signals in aging and longevity. Nat. Chem. Biol. 17, 1027–1036 (2021).

Article  CAS  PubMed  Google Scholar 

Kong, H. H. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850–859 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kapoor, B., Gulati, M., Rani, P. & Gupta, R. Psoriasis: interplay between dysbiosis and host immune system. Autoimmun. Rev. 21, 103169 (2022).

Article  CAS  PubMed  Google Scholar 

Prescott, S. L. The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming. World Allergy Organ J. 10, 29 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Meisel, J. S. Commensal microbiota modulate gene expression in the skin. Microbiome 6, 20 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Hu, L. Epidermal dysfunction leads to an age-associated increase in levels of serum inflammatory cytokines. J. Invest. Dermatol. 137, 1277–1285 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hibbert, S. A., Watson, R. E. B., Griffiths, C. E. M., Gibbs, N. K. & Sherratt, M. J. Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins. Cell Signal. 54, 191–199 (2019).

Article  CAS  PubMed  Google Scholar 

Pomatto, L. C. D. & Davies, K. J. A. The role of declining adaptive homeostasis in ageing. J. Physiol. 595, 7275–7309 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsitsipatis, D. Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span. Aging Cell 21, e13609 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liang, W. Skin chronological aging drives age-related bone loss via secretion of cystatin-A. Nat. Aging 2, 906–922 (2022).

Article  CAS  PubMed  Google Scholar 

Wen, S., Elias, P. M., Wakefield, J. S., Mauro, T. M. & Man, M. The link between cutaneous inflammation and cognitive impairment. J. Eur. Acad. Dermatol. Venereol. 36, 1705–1712 (2022).

Article  CAS  PubMed  Google Scholar 

Brash, D. E. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc. Natl Acad. Sci. USA 88, 10124–10128 (1991).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Alcolea, M. P. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16, 612–619 (2014).

Article  Google Scholar 

Kim, M. Investigation of age-related changes in the skin microbiota of korean women. Microorganisms 8, 1581 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Huang, S. Human skin, oral, and gut microbiomes predict chronological age. mSystems 5, e00630–19 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Stacy, A. & Belkaid, Y. Microbial guardians of skin health. Science 363, 227–228 (2019).

Article  CAS  PubMed  Google Scholar 

Chng, K. R. Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare. Nat. Microbiol. 1, 16106 (2016).

Article  CAS  PubMed  Google Scholar 

Lunjani, N., Hlela, C. & O’Mahony, L. Microbiome and skin biology. Curr. Opin. Allergy Clin. Immunol. 19, 328–333 (2019).

Article  PubMed  Google Scholar 

Palmer, C. N. A. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).

Article  CAS  PubMed  Google Scholar 

Ascott, A. Atopic eczema and major cardiovascular outcomes: a systematic review and meta-analysis of population-based studies. J. Allergy Clin. Immunol. 143, 1821–1829 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Holm, J. G. & Thomsen, S. F. Type 2 diabetes and psoriasis: links and risks. Psoriasis 9, 1–6 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Yang, B. & Man, M. -Q. Improvement in cutaneous conditions can benefit some health conditions in the elderly. Clin. Inter. Aging 18, 2031–2040 (2023).

Article  CAS  Google Scholar 

Kim, H. O., Kim, H. -S., Youn, J. -C., Shin, E. -C. & Park, S. Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays. J. Transl. Med. 9, 113 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dokoshi, T. Skin inflammation activates intestinal stromal fibroblasts and promotes colitis. J. Clin. Invest. 131, e147614 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dokoshi, T. Dermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice. Nat. Commun. 15, 3009 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Larson, P. J. Associations of the skin, oral and gut microbiome with aging, frailty and infection risk reservoirs in older adults. Nat. Aging 2, 941–955 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Solak, E. Ö. The relationship between the severity of coronary artery disease and skin measurement parameters. Skin Res. Technol. 27, 101–107 (2021).

Article  Google Scholar 

Bocheva, G., Slominski, R. M. & Slominski, A. T. The impact of vitamin D on skin aging. Int. J. Mol. Sci. 22, 9097 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Blatt, N. L., Khaiboullin, T. I., Lombardi, V. C., Rizvanov, A. A. & Khaiboullina, S. F. The skin–brain connection hypothesis, bringing together CCL27-mediated T-cell activation in the skin and neural cell damage in the Adult Brain. Front. Immunol. 7, 683 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Ramaraj, J. A. & Narayan, S. Anti-aging strategies and topical delivery of biopolymer-based nanocarriers for skin cancer treatment. Curr. Aging Sci. 17, 31–48 (2023).

Nishikori, S. Resistance training rejuvenates aging skin by reducing circulating inflammatory factors and enhancing dermal extracellular matrices. Sci. Rep. 13, 10214 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Furman, D. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rizwan, M. Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: a randomized controlled trial. Br. J. Dermatol. 164, 154–162 (2011).

Article  CAS  PubMed  Google Scholar 

Charoenchon, N. Ultraviolet radiation‐induced degradation of dermal extracellular matrix and protection by green tea catechins: a randomized controlled trial. Clin. Exp. Dermatol. 47, 1314–1323 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Sorbara, M. T. & Pamer, E. G. Microbiome-based therapeutics. Nat. Rev. Microbiol. 20, 365–380 (2022).

Article  CAS  PubMed  Google Scholar 

Svobodova, A., Psotova, J. & Walterova, D. Natural phenolics in the prevention of UV-induced skin damage. A review. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 147, 137–145 (2003).

Article  CAS  PubMed  Google Scholar 

Ye, L. A topical emollient mitigates the progression of cognitive impairment in the elderly: a randomized, open‐label pilot trial. J. Eur. Acad. Dermatol. Venereol. 36, 1382–1388 (2022).

Article  CAS  PubMed  Google Scholar 

Barnes, R. P. Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening. Nat. Struct. Mol. Biol. 29, 639–652 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Picca, A., Faitg, J., Auwerx, J., Ferrucci, L. & D’Amico, D. Mitophagy in human health, ageing and disease. Nat. Metab. 5, 2047–2061 (2023).

Article  PubMed  Google Scholar 

D’Amico, D. Impact of the natural compound urolithin A on health, disease, and aging. Trends Mol. Med. 27, 687–699 (2021).

Article  PubMed  Google Scholar 

Liu, W. et al. Urolithin A protects human dermal fibroblasts from UVA-induced photoaging through NRF2 activation and mitophagy. J. Photochem. Photobiol. B 232, 112462 (2022).

Article  CAS  PubMed  Google Scholar 

Harrington, J. S., Ryter, S. W., Plataki, M., Price, D. R. & Choi, A. M. K. Mitochondria in health, disease, and aging. Physiol. Rev. 103, 2349–2422 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pietrocola, F. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015).

Article  CAS  PubMed  Google Scholar 

Dańczak‐Pazdrowska, A. Cellular senescence in skin‐related research: targeted signaling pathways and naturally occurring therapeutic agents. Aging Cell 22, e13845 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Qin, D. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell. Physiol. Biochem. 46, 1849–1860 (2018).

Article  CAS  PubMed  Google Scholar 

Chung, C. L. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Geroscience 41, 861–869 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mannick, J. B. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2, 250–262 (2021).

Article  Google Scholar 

Mannick, J. B. & Lamming, D. W. Targeting the biology of aging with mTOR inhibitors. Nat. Aging 3, 642–660 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hickson, L. J. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Takaya, K. & Kishi, K. Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo. Biogerontology 25, 691–704 (2024).

Article  CAS  PubMed  Google Scholar 

Zhang, S. & Duan, E. Fighting against skin aging. Cell Transplant. 27, 729–738 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005).

Article  CAS  PubMed  Google Scholar 

Makrantonaki, E. & Zouboulis, C. C. Molecular mechanisms of skin aging. Ann. N. Y. Acad. Sci. 1119, 40–50 (2007).

Article  CAS  PubMed  Google Scholar 

Chen, C. -C. Regenerative hair waves in aging mice and extra-follicular modulators follistatin, Dkk1, and Sfrp4. J. Invest. Dermatol. 134, 2086–2096 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moqri, M. Validation of biomarkers of aging. Nat. Med. 30, 360–372 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ressler, S. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5, 379–389 (2006).

Article  CAS  PubMed  Google Scholar 

Prieur, A., Besnard, E., Babled, A. & Lemaitre, J. -M. p53 and p16^INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression. Nat. Commun. 2, 473 (2011).

Article  PubMed  Google Scholar 

Eberhardt, K. Raman and infrared spectroscopy differentiate senescent from proliferating cells in a human dermal fibroblast 3D skin model. Analyst 142, 4405–4414 (2017).

Article  CAS  PubMed  Google Scholar 

Sayed, N. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nat. Aging 1, 598–615 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Brunet, A. Old and new models for the study of human ageing. Nat. Rev. Mol. Cell Biol. 21, 491–493 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Albouy, M. Skin-protective biological activities of bio-fermented Aframomum angustifolium extract by a consortium of microorganisms. Front. Pharm. 14, 1303198 (2023).

Article  CAS  Google Scholar 

Hong, Z. -X. Bioengineered skin organoids: from development to applications. Mil. Med. Res. 10, 40 (2023).

PubMed  PubMed Central  Google Scholar 

Pitrez, P. R. et al. Cellular reprogramming as a tool to model human aging in a dish. Nat. Commun. 15, 1816 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zou, Z. et al. A single-cell transcriptomic atlas of human skin aging. Dev. Cell 56, 383–397 (2021).

Article  CAS  PubMed  Google Scholar 

Schepps, S. et al. Skin in the game: a review of single-cell and spatial transcriptomics in dermatological research. Clin. Chem. Lab. Med. 62, 1880–1891 (2024).

Article  CAS  PubMed  Google Scholar