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Reviews in Endocrine and Metabolic Disorders
Published in: Reviews in Endocrine and Metabolic Disorders 3/2016

01-09-2016

Biomarkers of skin aging

Authors: Theodora Kanaki, Evgenia Makrantonaki, Christos C. Zouboulis

Published in: Reviews in Endocrine and Metabolic Disorders | Issue 3/2016

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Abstract

Aging is a complex process not only influenced by inherited but also by several environmental factors. It is characterized by a progressive loss of function in multiple tissues, which leads to an increased probability of death. On the other hand, several morphological and histological changes are registered in aged skin that is mostly dependent on the cumulative exposure in environmental aging promoters, such as ultraviolet radiation. Understanding of individual pathogenesis and introduction of preventive measurements require objective assessment, i.e., the administration of biomarkers. Because of the complexity of skin aging, the exact definition of biomarkers is a major research challenge. In this article, we summarize the basic knowledge involving skin aging and its biomarkers.
Literature
1.
Maroso EJ. Physiological system markers of aging. Exp Gerontol. 1988;23:391–4.CrossRef
2.
Makrantonaki E, Brink TC, Zampeli V, Elewa RM, Mlody B, Hossini AM, et al. Identification of biomarkers of human skin ageing in both genders. Wnt signalling—a label of skin ageing? PLoS One. 2012;7, e50393.PubMedPubMedCentralCrossRef
3.
4.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92:9363–7.PubMedPubMedCentralCrossRef
5.
Yaar M, Eller MS, Gilchrest BA. Fifty years of skin aging. J Investig Dermatol Symp Proc. 2002;7:51–8.PubMedCrossRef
6.
Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc. 1990;65:375–98.PubMedCrossRef
7.
8.
Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992;89:10114–8.PubMedPubMedCentralCrossRef
9.
Smith JR, Pereira-Smith OM. Replicative senescence: implications for in vivo aging and tumor suppression. Science. 1996;273:63–7.PubMedCrossRef
10.
Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science. 1999;286:774–9.PubMedCrossRef
11.
Miquel J. An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp Gerontol. 1998;33:113–26.PubMedCrossRef
12.
13.
Gems D, Partridge L. Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol. 2013;75:621–44.PubMedCrossRef
14.
15.
16.
17.
18.
McGrath JA, Eady RAJ, Pope FM. Anatomy and organization of human skin. In: Burns T, Breathnach S, Cox N, Griffiths C (eds) Rook’s Textbook of Dermatology. 8th Edition, 2013:Chapter 3.
19.
Makrantonaki E, Zouboulis CC. German National Genome Research Network 2. The skin as a mirror of the aging process in the human organism—state of the art and results of the aging research in the German National Genome Research Network 2 (NGFN-2). Exp Gerontol. 2007;42:879–86.PubMedCrossRef
20.
Zouboulis CC, Makrantonaki E. Clinical aspects and molecular diagnostics of skin aging. Clin Dermatol. 2011;29:3–14.PubMedCrossRef
21.
Makrantonaki E, Bekou V, Zouboulis CC. Genetics and skin aging. Dermatol Endocrinol. 2012;4:280–4.CrossRef
22.
Makrantonaki E, Schönknecht P, Hossini AM, Kaiser E, Katsouli MM, Adjaye J, et al. Skin and brain age together: the role of hormones in the ageing process. Exp Gerontol. 2010;45:801–13.PubMedCrossRef
23.
Cordisco S, Maurelli R, Bondanza S, Stefanini M, Zambruno G, Guerra L, et al. Bmi-1 reduction plays a key role in physiological and premature aging of primary human keratinocytes. J Invest Dermatol. 2010;130:1048–62.PubMedCrossRef
24.
Navarro C, Cau P, Levy N. Molecular bases of progeroid syndromes. Hum Mol Genet. 2006;15:R151–61.PubMedCrossRef
25.
Nikolakis G, Makrantonaki E, Zouboulis CC. Skin mirrors human aging. Horm Mol Biol Clin Investig. 2013;16:3–28.
26.
Makrantonaki E, Zouboulis CC. Molecular mechanisms of skin aging: state of the art. Ann N Y Acad Sci. 2007;1119:40–50.PubMedCrossRef
27.
28.
29.
30.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Therapeut. 2001;69:89–95.CrossRef
31.
32.
33.
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science. 2006;311:1257.PubMedCrossRef
34.
Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007;128:36–44.PubMedCrossRef
35.
Passarge E. Color atlas of genetics. Stuttgart: Thieme; 2007.
36.
37.
38.
Sfeir AJ, Chai W, Shay JW, Wright WE. Telomere-end processing the terminal nucleotides of human chromosomes. Mol Cell. 2005;18:131–8.PubMedCrossRef
39.
Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–52.PubMedCrossRef
40.
Wright WE, Shay JW. Historical claims and current interpretations of replicative aging. Nat Biotechnol. 2002;20:682–8.PubMedCrossRef
41.
Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107:67–77.PubMedCrossRef
42.
d’Adda di Fagagna F, Teo SH, Jackson SP. Functional links between telomeres and proteins of the DNA-damage response. Genes Dev. 2004;18:1781–1799.
43.
von Zglinicki T, Martin-Ruiz CM. Telomeres as biomarkers for ageing and age-related diseases. Curr Mol Med. 2005;5:197–203.CrossRef
44.
Herbig U, Sedivy JM. Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech Ageing Dev. 2006;127:16–24.PubMedCrossRef
45.
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–198.
46.
Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–56.PubMedCrossRef
47.
Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004;14:501–13.PubMedCrossRef
48.
49.
Drayton S, Peters G. Immortalisation and transformation revisited. Curr Opin Genet Dev. 2002;12:98–104.PubMedCrossRef
50.
Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene. 1998;16:1113–23.PubMedCrossRef
51.
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009;4:1798–806.PubMedCrossRef
52.
Severino J, Allen RG, Balin S, Balin A, Cristofalo VJ. Is beta- galactosidase staining a marker of senescence in vitro and in vivo? Exp Cell Res. 2000;257:162–71.PubMedCrossRef
53.
54.
Yang NC, Hu ML. The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol. 2005;40:813–9.PubMedCrossRef
55.
Yegorov YE, Akimov SS, Hass R, Zelenin AV, Prudovsky IA. Endogenous beta-galactosidase activity in continuously nonproliferating cells. Exp Cell Res. 1998;243:207–11.PubMedCrossRef
56.
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5:187–95.PubMedCrossRef
57.
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114:1299–307.PubMedPubMedCentralCrossRef
58.
Campisi J. d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40.PubMedCrossRef
59.
Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–6.PubMedPubMedCentralCrossRef
60.
61.
Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray analysis of replicative senescence. Curr Biol. 1999;9:939–45.PubMedCrossRef
62.
Vo TK, de Saint-Hubert M, Morrhaye G, Godard P, Geenen V, Martens HJ, et al. Transcriptomic biomarkers of the response of hospitalized geriatric patients admitted with heart failure. Comparison to hospitalized geriatric patients with infectious diseases or hip fracture. Mech Ageing Dev. 2011;132:131–9.PubMedCrossRef
63.
Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300.PubMedCrossRef
64.
Yu BP, Yang R. Critical evaluation of the free radical theory of aging. A proposal for the oxidative stress hypothesis. Ann N Y Acad Sci. 1996;786:1–11.PubMedCrossRef
65.
Kim YJ, Yokozawa T, Chung HY. Effects of energy restriction and fish oil supplementation on renal guanidino levels and antioxidant defences in aged lupus-prone B/W mice. Br J Nutr. 2005;93:835–44.PubMedCrossRef
66.
67.
Marzetti E, Hwang JC, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS, et al. Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta. 1800;2010:235–44.
68.
69.
Ishitsuka Y, Maniwa F, Koide C, Kato Y, Nakamura Y, Osawa T, et al. Increased halogenated tyrosine levels are useful markers of human skin ageing, reflecting proteins denatured by past skin inflammation. Clin Exp Dermatol. 2012;37:252–8.PubMedCrossRef
70.
Domigan NM, Charlton TS, Duncan MW, Winterbourn CC, Kettle AJ. Chlorination of tyrosyl residues in peptides by myeloperoxidase and human neutrophils. J Biol Chem. 1995;270:16542–8.PubMedCrossRef
71.
Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest. 1997;99:2075–81.PubMedPubMedCentralCrossRef
72.
Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.PubMedCrossRef
73.
74.
75.
Mets T, Bekaert E, Verdonk G. Similarity between in vitro and in vivo cellular aging. Mech Ageing Dev. 1983;22:71–8.PubMedCrossRef
76.
Cristofalo VJ, Pignolo RJ. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev. 1993;73:617–38.PubMed
77.
Gilchrest BA, Vrabel MA, Flynn E, Szabo G. Selective cultivation of human melanocytes from newborn and adult epidermis. J Invest Dermatol. 1984;83:370–6.PubMedCrossRef
78.
79.
80.
81.
82.
Lu CY, Lee HC, Fahn HJ, Wei YH. Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin. Mutat Res. 1999;423:11–21.PubMedCrossRef
83.
84.
Velarde MC, Flynn JM, Day NU, Melov S, Campisi J. Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypesin the skin. Aging (Albany NY). 2012;4:3–12.CrossRef
85.
Hruszkewycz AM. Evidence for mitochondrial DNA damage by lipid peroxidation. Biochem Biophys Res Commun. 1988;153:191–7.PubMedCrossRef
86.
Hruszkewycz AM, Bergtold DS. The 8-hydroxyguanine content of isolated mitochondria increases with lipid peroxidation. Mutat Res. 1990;244:123–8.PubMedCrossRef
87.
Waaijer ME, Parish WE, Strongitharm BH, van Heemst D, Slagboom PE, de Craen AJ, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012;11:722–5.PubMedPubMedCentralCrossRef
88.
89.
Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73.PubMedCrossRef
90.
91.
Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am J Med. 2007;120(10):835–40.PubMedCrossRef
92.
Roth J, Koch CA, Rother KI. In: DeGroot LJ, Jameson JL, editors. Endocrinology. 4th ed. Philadelphia: WB Saunders; 2001. p. 529–55.
93.
Alesci S, Koch CA, Bornstein SR, Pacak K. Adrenal androgens regulation and adrenopause. Endocr Regul. 2001;35(2):95–100.PubMed
94.
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760–4.PubMedCrossRef
95.
Gloth 3rd FM, Gundberg CM, Hollis BW, Haddad Jr JG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA. 1995;274(21):1683–6.PubMedCrossRef
96.
McKane WR, Khosla S, Egan KS, Robins SP, Burritt MF, Riggs BL. Role of calcium intake in modulating age-related increases in parathyroid function and bone resorption. J Clin Endocrinol Metab. 1996;81(5):1699–703.PubMed
97.
Avioli LV, McDonald JE, Lee SW. The influence of age on the intestinal absorption of 47-Ca absorption in post-menopausal osteoporosis. J Clin Invest. 1965;44(12):1960–7.PubMedPubMedCentralCrossRef
98.
Slovik DM, Adams JS, Neer RM, Holick MF, Potts Jr JT. Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients. N Engl J Med. 1981;305(7):372–4.PubMedCrossRef
99.
Gloth 3rd FM, Tobin JD. Vitamin D deficiency in older people. J Am Geriatr Soc. 1995;43(7):822–8.PubMedCrossRef
100.
Makrantonaki E, Vogel K, Fimmel S, Oeff M, Seltmann H, Zouboulis CC. Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro. Exp Gerontol. 2008;43:939–46.PubMedCrossRef
101.
Elewa RM, Abdallah M, Youssef N, Zouboulis CC. Aging-related changes in cutaneous corticotropin-releasing hormone system reflect a defective neuroendocrine-stress response in aging. Rejuvenation Res. 2012;15:366–73.PubMedCrossRef
102.
Elewa RM, Abdallah MA, Zouboulis CC. Age-associated skin changes in innate immunity markers reflect a complex interaction between aging mechanisms in the sebaceous gland. J Dermatol. 2015;42:467–76.PubMedCrossRef
103.
Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990;323:1–6.PubMedCrossRef
104.
Rittié L, Kang S, Voorhees JJ, Fisher GJ. Induction of collagen by estradiol: difference between sun-protected and photodamaged human skin in vivo. Arch Dermatol. 2008;144:1129–40.PubMedCrossRef
105.
Fuchs KO, Solis O, Tapawan R, Paranjpe J. The effects of an estrogen and glycolic acid cream on the facial skin of postmenopausal women: a randomized histologic study. Cutis. 2003;71:481–8.PubMed
106.
Patriarca MT, Goldman KZ, Dos Santos JM, Petri V, Simões RS, Soares Jr JM, et al. Effects of topical estradiol on the facial skin collagen of postmenopausal women under oral hormone therapy: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2007;130:202–5.PubMedCrossRef
107.
Sator PG, Schmidt JB, Sator MO, Huber JC, Hönigsmann H. The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas. 2001;39:43–55.PubMedCrossRef
108.
Sator PG, Sator MO, Schmidt JB, Nahavandi H, Radakovic S, Huber JC, et al. A prospective, randomized, double-blind, placebo-controlled study on the influence of a hormone replacement therapy on skin aging in postmenopausal women. Climacteric. 2007;10:320–34.PubMedCrossRef
Metadata
Title
Biomarkers of skin aging
Authors
Theodora Kanaki
Evgenia Makrantonaki
Christos C. Zouboulis
Publication date
01-09-2016
Publisher
Springer US
Published in
Reviews in Endocrine and Metabolic Disorders / Issue 3/2016
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI
https://doi.org/10.1007/s11154-016-9392-x

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