Aging of organs starts from the time of birth and continues throughout life. Aging of skin can be divided into two distinct types—intrinsic aging and extrinsic, based on the fact that the skin is the outermost organ exposed to the external environment. However, despite their different histological features and triggers, intrinsic and extrinsic aging share common biochemical mechanisms. β-galactosidase, p16^INK4a, and senescence-associated secretory phenotype (SASP) factors are detected in skin cells as biomarkers of senescence. In particular, inflammatory cytokines, the constituents of SASP, play pivotal roles in “inflammaging” which is a concept involving the relationship between aging and low-grade inflammation. In this review, the features of skin aging and its underlying mechanism of skin aging are summarized.

1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Experimental Cell Research 1961; 25(3): 585–621.

2. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nature reviews Molecular cell biology 2007; 8(9): 729–740. doi: 10.1038/nrm2233

3. Kuilman T, Michaloglou C, Mooi WJ, et al. The essence of senescence. Genes & Development 2010; 24(22): 2463–2479. doi: 10.1101/gad.1971610

4. He S, Sharpless NE. Senescence in health and disease. Cell 2017; 169(6): 1000–1011. doi: 10.1016/j.cell.2017.05.015

5. Krutmann J, Bouloc A, Sore G, et al. The skin aging exposome. Journal of Dermatological Science 2017; 85(3): 152–161. doi: 10.1016/j.jdermsci.2016.09.015

6. Mora Huertas AC, Schmelzer CE, Hoehenwarter W, et al. Molecular-level insights into aging processes of skin elastin. Biochimie 2016; 128-129: 163–173. doi: 10.1016/j.biochi.2016.08.010

7. Kligman AM. Perspectives and problems in cutaneous gerontology. Journal of Investigative Dermatology 1979; 73(1): 39–46. doi: 10.1111/1523-1747.ep12532758

8. Lavker RM, Zheng P, Dong G. Aged skin: A study by light, transmission electron, and scanning electron microscopy. Journal of Investigative Dermatology 1987; 88(S3): 44s-51s. doi: 10.1111/1523-1747.ep12468934

9. Luebberding S, Krueger N, Kerscher M. Age-related changes in skin barrier function—quantitative evaluation of 150 female subjects. International Journal of Cosmetic Science 2013; 35(2): 183–190. doi: 10.1111/ics.12024

10. Man M, Xin S, Song S, et al. Variation of skin surface pH, sebum content and stratum corneum hydration with age and gender in a large Chinese population. Skin Pharmacol Physiol 2009; 22(4): 190–199. doi: 10.1159/000231524

11. Makrantonaki E, Zouboulis CC, William J. Cunliffe Scientific Awards. Characteristics and pathomechanisms of endogenously aged skin. Dermatology 2007; 214: 352–360. doi: 10.1159/000100890

12. Moragas A, Castells C, Sans M. Mathematical morphologic analysis of aging-related epidermal changes. Analytical and Quantitative Cytology and Histology 1993; 15(2): 75–82.

13. Kohl E, Steinbauer J, Landthaler M, et al. Skin ageing. Journal of the European Academy of Dermatology and Venereology 2011; 25(8): 873–884. doi: 10.1111/j.1468-3083.2010.03963.x

14. Quan T, Shao Y, He T, et al. Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin. Journal of Investigative Dermatology 2010; 130(2): 415–424. doi: 10.1038/jid.2009.224

15. Castro MCR, Ramos-E-Silva M. Cutaneous infections in the mature patient. Clinics in Dermatology 2018; 36(2): 188–196. doi: 10.1016/j.clindermatol.2017.10.010

16. Laube S. Skin infections and ageing. Ageing Research Reviews 2004; 3(1): 69–89. doi: 10.1016/j.arr.2003.08.003

17. Wessman LL, Andersen LK, Davis MDP. Incidence of diseases primarily affecting the skin by age group: population-based epidemiologic study in Olmsted County, Minnesota, and comparison with age-specific incidence rates worldwide. International Journal of Dermatology 2018; 57(9): 1021–1034. doi: 10.1111/ijd.13904

18. Vukmanovic-Stejic M, Rustin MHA, Nikolich-Zugich J, et al. Immune responses in the skin in old age. Current Opinion in Immunology 2011; 23(4): 525–531. doi: 10.1016/j.coi.2011.05.008

19. Fitzgerald KA, Kagan JC. Toll-like receptors and the control of immunity. Cell 2020; 180(6): 1044–1066. doi: 10.1016/j.cell.2020.02.041

20. Shaw AC, Panda A, Joshi SR, et al. Dysregulation of human toll-like receptor function in aging. Age-ing Research Reviews 2011; 10(3): 346–353. doi: 10.1016/j.arr.2010.10.007

21. Panda A, Qian F, Mohanty S, et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. The Journal of Immunology 2010; 184(5): 2518–2527. doi: 10.4049/jimmunol.0901022

22. West HC, Bennett CL. Redefining the role of Langerhans cells as immune regulators within the skin. Frontiers in Immunology 2017; 8: 1941. doi: 10.3389/fimmu.2017.01941

23. Chambers ES, Vukmanovic-Stejic M. Skin barrier immunity and ageing. Immunology 2020; 160(2): 116–125. doi: 10.1111/imm.13152

24. Della Bella S, Bierti L, Presicce P, et al. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clinical Immunology 2007; 122(2): 220–228. doi: 10.1016/j.clim.2006.09.012

25. Mahbub S, Brubaker AL, Kovacs EJ. Aging of the innate immune system: an update. Current Immunology Reviews 2011; 7(1): 104–115. doi: 10.2174/157339511794474181

26. Cumberbatch M, Dearman RJ, Kimber I. Influence of ageing on Langerhans cell migration in mice: identification of a putative deficiency of epidermal interleukin-1β. Immunology 2002; 105(4): 466–477. doi: 10.1046/j.1365-2567.2002.01381.x

27. Pilkington SM, Ogden S, Eaton LH, et al. Lower levels of interleukin-1β gene expression are associated with impaired Langerhans’ cell migration in aged human skin. Immunology 2018; 153(1): 60–70. doi: 10.1111/imm.12810

28. Grolleau-Julius A, Harning EK, Abernathy LM, et al. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer research 2008; 68(15): 6341–6349. doi: 10.1158/0008-5472.CAN-07-5769

29. Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLA+ T cells are resident in normal skin. The Journal of Immunology 2006; 176(7): 4431–4439. doi: 10.4049/jimmunol.176.7.4431

30. Watanabe R, Gehad A, Yang C, et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Science Translational Medicine 2015; 7(279): 279ra39. doi: 10.1126/scitranslmed.3010302

31. Vissinga C, Nagelkerken L, Zijlstra J, et al. A decreased functional capacity of CD4+ T cells underlies the impaired DTH reactivity in old mice. Mechanisms of Ageing and Development 1990; 53(2): 127–139. doi: 10.1016/0047-6374(90)90065-n

32. Toichi E, Hanada K, Hosokawa T, et al. Age-related decline in humoral immunity caused by the selective loss of TH cells and decline in cellular immunity caused by the impaired migration of inflammatory cells without a loss of TDTH cells in SAMP1 mice. Mech. Mechanisms of Ageing and Develop-ment 1997; 99(3): 199–217. doi: 10.1016/s0047-6374(97)00100-0

33. Castle SC, Norman DC, Perls TT, et al. Analysis of cutaneous delayed-type hypersensitivity reaction and T cell proliferative response in elderly nursing home patients: an approach to identifying immunodeficient patients. Gerontology 1990; 36(4): 217–229. doi: 10.1159/000213203

34. Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity 2008; 29(6): 848–862. doi: 10.1016/j.immuni.2008.11.002

35. Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nature Reviews Immunology 2011; 11(4): 289–295. doi: 10.1038/nri2959

36. Minato N, Hattori M, Hamazaki Y. Physiology and pathology of T-cell aging. International Immunology 2020; 32(4): 223–231. doi: 10.1093/intimm/dxaa006

37. Thomas R, Wang W, Su D. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immunity & Ageing 2020; 17(1): 1–17. doi: 10.1186/s12979-020-0173-8

38. Kligman LH. Photoaging: manifestations, prevention, and treatment. Clinics in Geriatric Medicine 1989; 5(1): 235–251. doi: 10.1016/S0749-0690(18)30708-0

39. Kaur P. Interfollicular epidermal stem cells: identification, challenges, potential. Journal of Investigative Dermatology 2006; 126(7): 1450–1458.

40. Bosset S, Bonnet-Duquennoy M, Barré P, et al. Decreased expression of keratinocyte β1 integrins in chronically sun-exposed skin in vivo. British Journal of Dermatology 2003; 148(4): 770–778. doi: 10.1046/j.1365-2133.2003.05159.x

41. Kwon OS, Yoo HG, Han JH, et al. Photoaging-associated changes in epidermal proliferative cell fractions in vivo. Archives of Dermatological Research 2008; 300(1): 47–52. doi: 10.1007/s00403-007-0812-3

42. Griffiths CE, Russman AN, Majmudar G, et al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). New England Journal of Medicine 1993; 329(8): 530–535. doi: 10.1056/NEJM199308193290803

43. Fisher GJ, Wang Z, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. New England Journal of Medicine 1997; 337(20): 1419–1428. doi: 10.1056/NEJM199711133372003

44. Varani J, Spearman D, Perone P, et al. Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. The American Journal of Pathol-ogy 2001; 158(3): 931–942. doi: 10.1016/S0002-9440(10)64040-0

45. Craven NM, Watson RE, Jones CJ, et al. Clinical features of photodamaged human skin are associated with a reduction in collagen VII. British Journal of Dermatology 1997; 137(3): 344–350.

46. Contet-Audonneau JL, Jeanmaire C, Pauly G. A histological study of human wrinkle structures: comparison between sun-exposed areas of the face, with or without wrinkles, and sun-protected areas. British Journal of Dermatology 1999; 140(6): 1038–1047. doi: 10.1046/j.1365-2133.1999.02901.x

47. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426(6963): 194–198. doi: 10.1038/nature02118

48. Serrano M, Lin AW, McCurrach ME, et al. Oncogenic RAS provokes premature cell senescence associated with accumulation of p53 and p16(INK4a). Cell 1997; 88(5): 593–602. doi: 10.1016/S0092-8674(00)81902-9

49. Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences 1995; 92(20): 9363–9367. doi: 10.1073/pnas.92.20.9363

50. Chazal M, Marionnet C, Michel L, et al. P16(INK4A) is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation. Oncogene 2002; 21(17): 2652–2661. doi: 10.1038/sj.onc.1205349

51. Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of aging. The Journal of Clinical Investigation 2004; 114(9): 1299–1307. doi: 10.1172/JCI22475

52. Ressler S, Bartkova J, Niederegger H, et al. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 2006; 5(5): 379–389. doi: 10.1111/j.1474-9726.2006.00231.x

53. Waaijer MEC, Parish WE, Strongitharm BH, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell 2012; 11(4): 722–725. doi: 10.1111/j.1474-9726.2012.00837.x

54. Wang AS, Dreesen O. Biomarkers of cellular senescence and skin aging. Frontiers in Genetics 2018; 9: 247. doi: 10.3389/fgene.2018.00247

55. Tsurumi A, Li WX. Global heterochromatin loss: a unifying theory of aging? Epigenetics 2012; 7(7): 680–688. doi: 10.4161/epi.20540

56. Dreesen O, Stewart CL. Accelerated aging syndromes, are they relevant to normal human aging? Aging (Albany NY) 2011; 3(9): 889–895. doi: 10.18632/aging.100383

57. Grönniger E, Weber B, Heil O, et al. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genetics 2010; 6(5): e1000971. doi: 10.1371/journal.pgen.1000971

58. Acosta JC, O’Loghlen A, Banito A, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008; 133(6): 1006–1018. doi: 10.1016/j.cell.2008.03.038

59. Kuilman T, Michaloglou C, Vredeveld LCW, et al. Oncogene-induced senescence relayed by an inter-leukin-dependent inflammatory network. Cell 2008; 133(6): 1019–1031. doi: 10.1016/j.cell.2008.03.039

60. Wajapeyee N, Serra RW, Zhu X, et al. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 2008; 132(3): 363–374. doi: 10.1016/j.cell.2007.12.032

61. Davalos AR, Kawahara M, Malhotra GK, et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. Journal of Cell Biology 2013; 201(4): 613–629. doi: 10.1083/jcb.201206006

62. Biran A, Zada L, Abou Karam P, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell 2017; 16(4): 661–671. doi: 10.1111/acel.12592

63. Waldera Lupa DM, Kalfalah F, Safferling K, et al. Characterization of skin aging–associated secreted proteins (SAASP) produced by dermal fibroblasts isolated from intrinsically aged human skin. Journal of Investigative Dermatology 2015; 135(8): 1954–1968. doi: 10.1038/jid.2015.120

64. Franceschi C, Bonafè M, Valensin S, et al. Inflammaging: An evolutionary perspective on immunosenescence. Annals of the New York Academy of Sciences 2000; 908(1): 244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x

65. Giunta B, Fernandez F, Nikolic WV, et al. Inflammaging as a prodrome to Alzheimer’s disease. Journal of Neuroinflammation 2008; 5(1): 1–15. doi: 10.1186/1742-2094-5-51

66. De Martinis M, Franceschi C, Monti D, et al. Inflammageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Letters 2005; 579(10): 2035–2039. doi: 10.1016/j.febslet.2005.02.055

67. Salminen A, Huuskonen J, Ojala J, et al. Activation of innate immunity system during aging: NF-κB signaling is the molecular culprit of inflamm-aging. Ageing Research Reviews 2008; 7(2): 83–105. doi: 10.1016/j.arr.2007.09.002

68. Mishto M, Santoro A, Bellavista E, et al. Immuno-proteasomes and immunosenescence. Ageing Research Reviews 2003; 2(4): 419–432. doi: 10.1016/s1568-1637(03)00030-8

69. Fuente MDI, Miquel J. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflammaging. Current Pharmaceutical Design 2009; 15(26): 3003–3026. doi: 10.2174/138161209789058110

70. Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflammaging as two sides of the same coin: friends or foes? Frontiers in Immunology 2017; 8: 1960. doi: 10.3389/fimmu.2017.01960.

71. Xia S, Zhang X, Zheng S, et al. An update on inflammaging: mechanisms, prevention, and treatment. Journal of Immunology Research 2016; 2016: 8426874. doi: 10.1155/2016/8426874

72. Butcher SK, Lord JM. Stress responses and innate immunity: aging as a contributory factor. Aging Cell 2004; 3(4): 151–160. doi: 10.1111/j.1474-9728.2004.00103.x

73. Salvioli S, Capri M, Valensin S, et al. Inflammaging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Current Pharmaceutical Design 2006; 12(24): 3161–3171. doi: 10.2174/138161206777947470

74. Hewitt G, Jurk D, Marques FDM, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nature Communications 2012; 3(1): 1–9. doi: 10.1038/ncomms1708

75. Olivieri F, Albertini MC, Orciani M, et al. DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflammaging. Oncotarget 2015; 6(34): 35509–35521. doi: 10.18632/oncotarget.5899

76. Juhász G, Erdi B, Sass M, et al. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes & Development 2007; 21(23): 3061–3066. doi: 10.1101/gad.1600707

77. Jones DL, Rando TA. Emerging models and paradigms for stem cell ageing. Nature Cell Biology 2011; 13(5): 506–512. doi: 10.1038/ncb0511-506

78. Coppé JP, Rodier F, Patil CK, et al. Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. Journal of Biological Chemistry 2011; 286(42): 36396–36403. doi: 10.1074/jbc.M111.257071

79. Rodier F, Coppé JP, Patil CK, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biology 2009; 11(8): 973–979. doi: 10.1038/ncb1909

80. Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 2006; 444(7119): 638–642. doi: 10.1038/nature05327

81. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response independent regulator of the senescence-associated secretory phenotype. The EMBO Journal 2011; 30(8): 1536–1548. doi: 10.1038/emboj.2011.69

82. Wang P, Han L, Shen H, et al. Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation. Proceedings of the National Academy of Sciences 2014; 111(21): 7683–7688. doi: 10.1073/pnas.1310972111

83. Ghosh K, Capell BC. The senescence-associated secretory phenotype: critical effector in skin cancer and aging. Journal of Investigative Dermatology 2016; 136(11): 2133–2139. doi: 10.1016/j.jid.2016.06.621

84. Sebastian T, Malik R, Thomas S, et al. C/EBPβ cooperates with RB:E2F to implement RasV12-induced cellular senescence. The EMBO Journal 2005; 24(18): 3301–3312. doi: 10.1038/sj.emboj.7600789

85. Orjalo AV, Bhaumik D, Gengler BK, et al. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proceedings of the National Academy of Sciences 2009; 106(40): 17031–17036. doi: 10.1073/pnas.0905299106

86. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology 2013; 15(8): 978–990. doi: 10.1038/ncb2784

87. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular senescence: causes and consequences. Trends in Molecular Medicine 2010; 16(5): 238–246. doi: 10.1016/j.molmed.2010.03.003

88. Carlson ME, Conboy IM. Loss of stem cell regenerative capacity within aged niches. Aging Cell 2007; 6(3): 371–382. doi: 10.1111/j.1474-9726.2007.00286.x

89. Storey A, McArdle F, Friedmann PS, et al. Eicosapentaenoic acid and docosahexaenoic acid reduce UVB- and TNF-α-induced IL-8 secretion in keratinocytes and UVB-induced IL-8 in fibroblasts. Journal of Investigative Dermatology 2005; 124(1): 248–255. doi: 10.1111/j.0022-202X.2004.23543.x

90. Lewis DA, Spandau DF. UVB-induced activation of NF-κB is regulated by the IGF-1R and dependent on p38 MAPK. Journal of Investigative Dermatology 2008; 128(4): 1022–1029. doi: 10.1038/sj.jid.5701127

91. Lewis DA, Yi Q, Travers JB, et al. UVB-induced senescence in human keratinocytes requires a functional insulin-like growth factor-1 receptor and p53. Molecular Biology of the Cell 2008; 19(4): 1346–1353. doi: 10.1091/mbc.e07-10-1041

92. Johnson KE, Wulff BC, Oberyszyn TM, et al. Ul-traviolet light exposure stimulates HMGB1 release by keratinocytes. Archives of Dermatological Research 2013; 305(9): 805–815. doi: 10.1007/s00403-013-1401-2

93. Aioi A. Sirtuins in wound healing. Trends in Immunotherapy. 2019; 3(2): 89–95. doi: 10.24294/ti.v3.i2.122

94. Hayakawa T, Iwai M, Aoki S, et al. SIRT1 suppresses the senescence-associated secretory pheno-type through epigenetic gene regulation. PloS ONE 2015; 10(1): e0116480. doi: 10.1371/journal.pone.0116480

95. Kim HK. Protective effect of garlic on cellular senescence in UVB-exposed HaCaT human keratinocytes. Nutrients 2016; 8(8): 464. doi: 10.3390/nu8080464