porozendoОстеопороз и остеопатииOsteoporosis and Bone Diseases2072-26802311-0716Endocrinology Research Centre10.14341/osteo12331porozendo-12331Research ArticleНаучный обзорReviewНаследственные синдромы с признаками преждевременного старенияHereditary syndromes with signs of premature aginghttps://orcid.org/0000-0003-2320-1051ГолоунинаОльга ОлеговнаGolouninaOlga O.

студентка 2-го курса лечебного факультета

Student, Medical faculty

olga.golounina@mail.ruhttps://orcid.org/0000-0002-3026-6315ФадеевВалентин ВикторовичFadeevValentin V.

д.м.н., профессор, член-корреспондент РАН

MD, PhD, Professor

walfad@mail.ruhttps://orcid.org/0000-0002-6674-6441БелаяЖанна ЕвгеньевнаBelayaZhanna E.

доктор медицинских наук, профессор

MD, PhD, Professor

jannabelaya@gmail.comФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)Russian FederationФГБУ “Национальный медицинский исследовательский центр эндокринологии” МЗ РФРоссияEndocrinology Research CenterRussian Federation201901062020223418Copyright © Голоунина О.О., Фадеев В.В., Белая Ж.Е., 20192019Голоунина О.О., Фадеев В.В., Белая Ж.Е.Golounina O.O., Fadeev V.V., Belaya Z.E.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.osteo-endojournals.ru/jour/article/view/12331

Старение – мультифакторный биологический процесс, неизбежно затрагивающий каждого человека. Дегенеративные процессы, начинаясь на клеточном и молекулярном уровнях, постепенно влияют на изменение функциональных возможностей всех органов и систем. Прогероидные синдромы (от греч. progērōs – преждевременно состарившийся), или синдромы преждевременного старения, представляют собой клинически и генетически гетерогенную группу редких наследственных заболеваний, характеризующихся ускоренным старением организма. К прогериям и сегментарным прогероидным синдромам относят свыше десятка заболеваний, однако наиболее ярко признаки преждевременного старения проявляются при синдроме Хатчинсона–Гилфорда (прогерия детского возраста) и синдроме Вернера (прогерия взрослых). В представленном обзоре обобщены последние данные литературы, отражающие этиологию и клиническую картину прогерий и сегментарных прогероидных синдромов человека. На примере прогероидных синдромов рассмотрены молекулярные механизмы старения в целом. Обсуждаются современные возможности и потенциальные пути влияния на механизмы развития возрастных изменений. Дальнейшее изучение генетических причин, а также разработка методов лечения прогерий и сегментарных прогероидных синдромов может быть перспективным направлением для коррекции возрастных изменений человека и увеличения продолжительности жизни.

Aging is a multi-factor biological process that inevitably affects everyone. Degenerative processes, starting at the cellular and molecular levels, gradually influence the change in the functional capabilities of all organs and systems. Progeroid syndromes (from Greek. progērōs – prematurely old), or premature aging syndromes, represent clinically and genetically heterogeneous group of rare hereditary diseases characterized by accelerated aging of the body. Progeria and segmental progeroid syndromes include more than a dozen diseases, but the most clear signs of premature aging are evident in Hutchinson-Guilford Progeria Syndrome and Werner Syndrome. This review summarizes the latest scientific data reflecting the etiology and clinical picture of progeria and segmental progeroid syndromes in humans. Molecular mechanisms of aging are considered, using the example of progeroid syndromes. Modern possibilities and potential ways of influencing the mechanisms of the development of age-related changes are discussed. Further study of genetic causes, as well as the development of treatment for progeria and segmental progeroid syndromes, may be a promising direction for correcting age-related changes and increasing life expectancy.

преждевременное старениепрогериясиндром Хатчинсона–Гилфордасиндром ВернераламинопатиителомерылонафарнибPremature agingprogeriaHutchinson-Guilford Progeria SyndromeWerner SyndromelaminopathiestelomeresLonafarnibReferencesLópez-Otín C, Blasco MA, Partridge L, et al. The Hallmarks of Aging. Cell. 2013;153(6):1194-1217. doi: https://doi.org/10.1016/j.cell.2013.05.039López-Otín C, Blasco MA, Partridge L, et al. The Hallmarks of Aging. Cell. 2013;153(6):1194-1217. doi: https://doi.org/10.1016/j.cell.2013.05.039Kudlow BA, Kennedy BK, Monnat RJ, Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol. 2007;8(5):394-404. doi: https://doi.org/10.1038/nrm2161Kudlow BA, Kennedy BK, Monnat RJ, Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol. 2007;8(5):394-404. doi: https://doi.org/10.1038/nrm2161Hutchinson J. Congenital Absence of Hair and Mammary Glands with Atrophic Condition of the Skin and its Appendages, in a Boy whose Mother had been almost wholly Bald from Alopecia Areata from the age of Six. Med Chir Trans. 1886;69:473-477. doi: https://doi.org/10.1177/095952878606900127Hutchinson J. Congenital Absence of Hair and Mammary Glands with Atrophic Condition of the Skin and its Appendages, in a Boy whose Mother had been almost wholly Bald from Alopecia Areata from the age of Six. Med Chir Trans. 1886;69:473-477. doi: https://doi.org/10.1177/095952878606900127Gilford H. On a Condition of Mixed Premature and Immature Development. Med Chir Trans. 1897;80:17-46 25. doi: https://doi.org/10.1177/095952879708000105Gilford H. On a Condition of Mixed Premature and Immature Development. Med Chir Trans. 1897;80:17-46 25. doi: https://doi.org/10.1177/095952879708000105Werner O. On cataract in conjunction with scleroderma. In: Salk D, Fujiwara Y, Martin GM, editors. Werner’s Syndrome and Human Aging. Advances in Experimental Medicine and Biology. Vol. 190. Boston: Springer; 1985. p. 1-14. doi: https://doi.org/10.1007/978-1-4684-7853-2_1.Werner O. On cataract in conjunction with scleroderma. In: Salk D, Fujiwara Y, Martin GM, editors. Werner’s Syndrome and Human Aging. Advances in Experimental Medicine and Biology. Vol. 190. Boston: Springer; 1985. p. 1-14. doi: https://doi.org/10.1007/978-1-4684-7853-2_1.Rautenstrauch T, Snigula F. Progeria: a cell culture study and clinical report of familial incidence. Eur J Pediatr. 1977;124(2):101-111. doi: https://doi.org/10.1007/bf00477545Rautenstrauch T, Snigula F. Progeria: a cell culture study and clinical report of familial incidence. Eur J Pediatr. 1977;124(2):101-111. doi: https://doi.org/10.1007/bf00477545Wiedemann HR. An unidentified neonatal progeroid syndrome: follow-up report. Eur J Pediatr. 1979;130(1):65-70. doi: https://doi.org/10.1007/bf00441901Wiedemann HR. An unidentified neonatal progeroid syndrome: follow-up report. Eur J Pediatr. 1979;130(1):65-70. doi: https://doi.org/10.1007/bf00441901Wambach JA, Wegner DJ, Patni N, et al. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018;103(6):968-975. doi: https://doi.org/10.1016/j.ajhg.2018.10.010Wambach JA, Wegner DJ, Patni N, et al. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018;103(6):968-975. doi: https://doi.org/10.1016/j.ajhg.2018.10.010Paolacci S, Li Y, Agolini E, et al. Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. J Med Genet. 2018;55(12):837-846. doi: https://doi.org/10.1136/jmedgenet-2018-105528Paolacci S, Li Y, Agolini E, et al. Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. J Med Genet. 2018;55(12):837-846. doi: https://doi.org/10.1136/jmedgenet-2018-105528Paolacci S, Bertola D, Franco J, et al. Wiedemann-Rautenstrauch syndrome: A phenotype analysis. Am J Med Genet A. 2017;173(7):1763-1772. doi: https://doi.org/10.1002/ajmg.a.38246Paolacci S, Bertola D, Franco J, et al. Wiedemann-Rautenstrauch syndrome: A phenotype analysis. Am J Med Genet A. 2017;173(7):1763-1772. doi: https://doi.org/10.1002/ajmg.a.38246Becerra CH, Contreras-Garcia GA, Perez Vera LA, et al. Wiedemann-Rautenstrauch syndrome prenatal diagnosis. J Perinatol. 2014;34(12):954-956. doi: https://doi.org/10.1038/jp.2014.156Becerra CH, Contreras-Garcia GA, Perez Vera LA, et al. Wiedemann-Rautenstrauch syndrome prenatal diagnosis. J Perinatol. 2014;34(12):954-956. doi: https://doi.org/10.1038/jp.2014.156Beauregard-Lacroix E, Salian S, Kim H, et al. A variant of neonatal progeroid syndrome, or Wiedemann-Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL. Eur J Hum Genet. 2020;28(4):461-468. doi: https://doi.org/10.1038/s41431-019-0539-6Beauregard-Lacroix E, Salian S, Kim H, et al. A variant of neonatal progeroid syndrome, or Wiedemann-Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL. Eur J Hum Genet. 2020;28(4):461-468. doi: https://doi.org/10.1038/s41431-019-0539-6Gargiuli C, Schena E, Mattioli E, et al. Lamins and bone disorders: current understanding and perspectives. Oncotarget. 2018;9(32):22817-22831. doi: https://doi.org/10.18632/oncotarget.25071Gargiuli C, Schena E, Mattioli E, et al. Lamins and bone disorders: current understanding and perspectives. Oncotarget. 2018;9(32):22817-22831. doi: https://doi.org/10.18632/oncotarget.25071Дадали Е.Л., Билева Д.С., Угаров И.В. Клинико-генетическая характеристика наследственных ламинопатий. // Анналы клинической и экспериментальной неврологии. — 2008. — Т. 2. — №4. — С. 28-33. [Dadaly EL, Bileva DS, Ugarov IV. Clinical and genetic characteristics of hereditary laminopathies. Annaly klinicheskoy i eksperimental’noy nevrologii. 2008;2(4):28-33. (In Russ.)]Дадали Е.Л., Билева Д.С., Угаров И.В. Клинико-генетическая характеристика наследственных ламинопатий. // Анналы клинической и экспериментальной неврологии. — 2008. — Т. 2. — №4. — С. 28-33. [Dadaly EL, Bileva DS, Ugarov IV. Clinical and genetic characteristics of hereditary laminopathies. Annaly klinicheskoy i eksperimental’noy nevrologii. 2008;2(4):28-33. (In Russ.)]Gonzalo S, Kreienkamp R, Askjaer P. Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev. 2017;33:18-29. doi: https://doi.org/10.1016/j.arr.2016.06.007Gonzalo S, Kreienkamp R, Askjaer P. Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev. 2017;33:18-29. doi: https://doi.org/10.1016/j.arr.2016.06.007Ashapkin VV, Kutueva LI, Kurchashova SY, Kireev II. Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging? Front Genet. 2019;10. doi: https://doi.org/10.3389/fgene.2019.00455Ashapkin VV, Kutueva LI, Kurchashova SY, Kireev II. Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging? Front Genet. 2019;10. doi: https://doi.org/10.3389/fgene.2019.00455Turgay Y, Eibauer M, Goldman AE, et al. The molecular architecture of lamins in somatic cells. Nature. 2017;543(7644):261-264. doi: https://doi.org/10.1038/nature21382Turgay Y, Eibauer M, Goldman AE, et al. The molecular architecture of lamins in somatic cells. Nature. 2017;543(7644):261-264. doi: https://doi.org/10.1038/nature21382Лаврушкина С.В., Овсянникова Н.Л., Юдина А.С., и др. Канцерогенез и старение: взгляд со стороны ядерной ламины. // Цитология. — 2018. — Т. 60. — №11. — С. 892-894. [Lavrushlina SV, Ovsyannikova NL, Yudina AS, et al. Carcinogenesis and ageing: a view from nuclear lamina. Cell and tissue biology. 2018;60(11):892-894. (In Russ.)] doi: https://doi.org/10.1134/S0041377118110056.Лаврушкина С.В., Овсянникова Н.Л., Юдина А.С., и др. Канцерогенез и старение: взгляд со стороны ядерной ламины. // Цитология. — 2018. — Т. 60. — №11. — С. 892-894. [Lavrushlina SV, Ovsyannikova NL, Yudina AS, et al. Carcinogenesis and ageing: a view from nuclear lamina. Cell and tissue biology. 2018;60(11):892-894. (In Russ.)] doi: https://doi.org/10.1134/S0041377118110056.Swahari V, Nakamura A. Speeding up the clock: The past, present and future of progeria. Dev Growth Differ. 2016;58(1):116-130. doi: https://doi.org/10.1111/dgd.12251Swahari V, Nakamura A. Speeding up the clock: The past, present and future of progeria. Dev Growth Differ. 2016;58(1):116-130. doi: https://doi.org/10.1111/dgd.12251Piekarowicz K, Machowska M, Dzianisava V, Rzepecki R. Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment. Cells. 2019;8(2):88. doi: https://doi.org/10.3390/cells8020088Piekarowicz K, Machowska M, Dzianisava V, Rzepecki R. Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment. Cells. 2019;8(2):88. doi: https://doi.org/10.3390/cells8020088Politano L, Lattanzi G, Benedetti S, et al. Emerging perspectives on laminopathies. Cell Health Cytoskelet. 2016:25. doi: https://doi.org/10.2147/chc.s59507Politano L, Lattanzi G, Benedetti S, et al. Emerging perspectives on laminopathies. Cell Health Cytoskelet. 2016:25. doi: https://doi.org/10.2147/chc.s59507Hamczyk MR, del Campo L, Andrés V. Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome. Annu Rev Physiol. 2018;80(1):27-48. doi: https://doi.org/10.1146/annurev-physiol-021317-121454Hamczyk MR, del Campo L, Andrés V. Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome. Annu Rev Physiol. 2018;80(1):27-48. doi: https://doi.org/10.1146/annurev-physiol-021317-121454Navarro CL, Esteves-Vieira V, Courrier S, et al. New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update. Eur J Hum Genet. 2013;22(8):1002-1011. doi: https://doi.org/10.1038/ejhg.2013.258Navarro CL, Esteves-Vieira V, Courrier S, et al. New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update. Eur J Hum Genet. 2013;22(8):1002-1011. doi: https://doi.org/10.1038/ejhg.2013.258McKenna T, Sola Carvajal A, Eriksson M. Skin Disease in Laminopathy-Associated Premature Aging. J Invest Dermatol. 2015;135(11):2577-2583. doi: https://doi.org/10.1038/jid.2015.295McKenna T, Sola Carvajal A, Eriksson M. Skin Disease in Laminopathy-Associated Premature Aging. J Invest Dermatol. 2015;135(11):2577-2583. doi: https://doi.org/10.1038/jid.2015.295Filesi I, Gullotta F, Lattanzi G, et al. Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy. Physiol Genomics. 2005;23(2):150-158. doi: https://doi.org/10.1152/physiolgenomics.00060.2005Filesi I, Gullotta F, Lattanzi G, et al. Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy. Physiol Genomics. 2005;23(2):150-158. doi: https://doi.org/10.1152/physiolgenomics.00060.2005Yaou RB, Navarro C, Quijano-Roy S, et al. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet. 2011;19(6):647-654. doi: https://doi.org/10.1038/ejhg.2010.256Yaou RB, Navarro C, Quijano-Roy S, et al. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet. 2011;19(6):647-654. doi: https://doi.org/10.1038/ejhg.2010.256Соркина Е.Л., Тюльпаков А.Н. Наследственные и приобретенные липодистрофии: молекулярно-генетические и аутоиммунные механизмы. // Ожирение и метаболизм. — 2018. — Т. 15. — №1. — С. 39-42. [Sorkina EL, Tyulpakov AN. Inherited and acquired lipodystrophies: molecular-genetic and autoimmune mechanisms. Obesity and metabolism. 2018;15(1):39-42. (In Russ.)] doi: https://doi.org/10.14341/OMET2018139-42Соркина Е.Л., Тюльпаков А.Н. Наследственные и приобретенные липодистрофии: молекулярно-генетические и аутоиммунные механизмы. // Ожирение и метаболизм. — 2018. — Т. 15. — №1. — С. 39-42. [Sorkina EL, Tyulpakov AN. Inherited and acquired lipodystrophies: molecular-genetic and autoimmune mechanisms. Obesity and metabolism. 2018;15(1):39-42. (In Russ.)] doi: https://doi.org/10.14341/OMET2018139-42Bachrati CZ, Hickson ID. RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem J. 2003;374(Pt 3):577-606. doi: https://doi.org/10.1042/BJ20030491Bachrati CZ, Hickson ID. RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem J. 2003;374(Pt 3):577-606. doi: https://doi.org/10.1042/BJ20030491Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem. 2014;83:519-552. doi: https://doi.org/10.1146/annurev-biochem-060713-035428Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem. 2014;83:519-552. doi: https://doi.org/10.1146/annurev-biochem-060713-035428Guo RB, Rigolet P, Ren H, et al. Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein. Nucleic Acids Res. 2007;35(18):6297-6310. doi: https://doi.org/10.1093/nar/gkm536Guo RB, Rigolet P, Ren H, et al. Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein. Nucleic Acids Res. 2007;35(18):6297-6310. doi: https://doi.org/10.1093/nar/gkm536Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer Lett. 2006;232(1):107-120. doi: https://doi.org/10.1016/j.canlet.2005.07.042Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer Lett. 2006;232(1):107-120. doi: https://doi.org/10.1016/j.canlet.2005.07.042Shamanna RA, Croteau DL, Lee JH, Bohr VA. Recent Advances in Understanding Werner Syndrome. F1000Res. 2017;6:1779. doi: https://doi.org/10.12688/f1000research.12110.1Shamanna RA, Croteau DL, Lee JH, Bohr VA. Recent Advances in Understanding Werner Syndrome. F1000Res. 2017;6:1779. doi: https://doi.org/10.12688/f1000research.12110.1O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11(3):171-181. doi: https://doi.org/10.1038/nrm2848O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11(3):171-181. doi: https://doi.org/10.1038/nrm2848Johnson JE, Cao K, Ryvkin P, et al. Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential. Nucleic Acids Res. 2010;38(4):1114-1122. doi: https://doi.org/10.1093/nar/gkp1103Johnson JE, Cao K, Ryvkin P, et al. Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential. Nucleic Acids Res. 2010;38(4):1114-1122. doi: https://doi.org/10.1093/nar/gkp1103Драпкина О.М., Шепель Р.Н. Теломеры и теломеразный комплекс. Основные клинические проявления генетического сбоя // Кардиоваскулярная терапия и профилактика. – 2015. Т.14. – №1. – С. 70-77. [Drapkina OM, Shepel RN. Telomeres and telomerase complex. The main clinical manifestation of genetic malfunctioning. Cardiovascular Therapy and Prevention 2015;14(1):70-77. (In Russ.)] doi: https://doi.org/10.15829/1728-8800-2015-1-70-77Драпкина О.М., Шепель Р.Н. Теломеры и теломеразный комплекс. Основные клинические проявления генетического сбоя // Кардиоваскулярная терапия и профилактика. – 2015. Т.14. – №1. – С. 70-77. [Drapkina OM, Shepel RN. Telomeres and telomerase complex. The main clinical manifestation of genetic malfunctioning. Cardiovascular Therapy and Prevention 2015;14(1):70-77. (In Russ.)] doi: https://doi.org/10.15829/1728-8800-2015-1-70-77Tang W, Robles AI, Beyer RP, et al. The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet. 2016;25(10):2060-2069. doi: https://doi.org/10.1093/hmg/ddw079Tang W, Robles AI, Beyer RP, et al. The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet. 2016;25(10):2060-2069. doi: https://doi.org/10.1093/hmg/ddw079Ishikawa N, Nakamura K-I, Izumiyama-Shimomura N, et al. Accelerated <i>in vivo</i> epidermal telomere loss in Werner syndrome. Aging. 2011;3(4):417-429. doi: https://doi.org/10.18632/aging.100315Ishikawa N, Nakamura K-I, Izumiyama-Shimomura N, et al. Accelerated <i>in vivo</i> epidermal telomere loss in Werner syndrome. Aging. 2011;3(4):417-429. doi: https://doi.org/10.18632/aging.100315Maierhofer A, Flunkert J, Oshima J, et al. Accelerated epigenetic aging in Werner syndrome. Aging. 2017;9(4):1143-1152. doi: https://doi.org/10.18632/aging.101217Maierhofer A, Flunkert J, Oshima J, et al. Accelerated epigenetic aging in Werner syndrome. Aging. 2017;9(4):1143-1152. doi: https://doi.org/10.18632/aging.101217Zhang W, Li J, Suzuki K, et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348(6239):1160-1163. doi: https://doi.org/10.1126/science.aaa1356Zhang W, Li J, Suzuki K, et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348(6239):1160-1163. doi: https://doi.org/10.1126/science.aaa1356Sarbacher CA, Halper JT. Connective Tissue and Age-Related Diseases. Subcell Biochem. 2019;91:281-310. doi: https://doi.org/10.1007/978-981-13-3681-2_11Sarbacher CA, Halper JT. Connective Tissue and Age-Related Diseases. Subcell Biochem. 2019;91:281-310. doi: https://doi.org/10.1007/978-981-13-3681-2_11Masala MV, Scapaticci S, Olivieri C, et al. Epidemiology and clinical aspects of Werner’s syndrome in North Sardinia: description of a cluster. Eur J Dermatol. 2007;17(3):213-216. doi: https://doi.org/10.1684/ejd.2007.0155Masala MV, Scapaticci S, Olivieri C, et al. Epidemiology and clinical aspects of Werner’s syndrome in North Sardinia: description of a cluster. Eur J Dermatol. 2007;17(3):213-216. doi: https://doi.org/10.1684/ejd.2007.0155Yokote K, Chanprasert S, Lee L, et al. WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Hum Mutat. 2017;38(1):7-15. doi: https://doi.org/10.1002/humu.23128Yokote K, Chanprasert S, Lee L, et al. WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Hum Mutat. 2017;38(1):7-15. doi: https://doi.org/10.1002/humu.23128Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science. 2005;307(5710):720-724. doi: https://doi.org/10.1126/science.1099593Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science. 2005;307(5710):720-724. doi: https://doi.org/10.1126/science.1099593Oshima J, Sidorova JM, Monnat RJ, Jr. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017;33:105-114. doi: https://doi.org/10.1016/j.arr.2016.03.002Oshima J, Sidorova JM, Monnat RJ, Jr. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017;33:105-114. doi: https://doi.org/10.1016/j.arr.2016.03.002Lessel D, Kubisch C. Hereditary Syndromes with Signs of Premature Aging. Dtsch Arztebl Int. 2019;116(29-30):489-496. doi: https://doi.org/10.3238/arztebl.2019.0489Lessel D, Kubisch C. Hereditary Syndromes with Signs of Premature Aging. Dtsch Arztebl Int. 2019;116(29-30):489-496. doi: https://doi.org/10.3238/arztebl.2019.0489Ozturk M, Akdeniz N, Ayakta H, Kosem M. A brother and sister with Werner’s syndrome demonstrating extensive tendon calcification and sacroiliitis. Clin Exp Dermatol. 2006;31(4):615-616. doi: https://doi.org/10.1111/j.1365-2230.2006.02130.xOzturk M, Akdeniz N, Ayakta H, Kosem M. A brother and sister with Werner’s syndrome demonstrating extensive tendon calcification and sacroiliitis. Clin Exp Dermatol. 2006;31(4):615-616. doi: https://doi.org/10.1111/j.1365-2230.2006.02130.xHonjo S, Yokote K, Fujimoto M, et al. Clinical outcome and mechanism of soft tissue calcification in Werner syndrome. Rejuvenation Res. 2008;11(4):809-819. doi: https://doi.org/10.1089/rej.2007.0649Honjo S, Yokote K, Fujimoto M, et al. Clinical outcome and mechanism of soft tissue calcification in Werner syndrome. Rejuvenation Res. 2008;11(4):809-819. doi: https://doi.org/10.1089/rej.2007.0649Leone A, Costantini AM, Brigida R, et al. Soft-tissue mineralization in Werner syndrome. Skeletal Radiol. 2005;34(1):47-51. doi: https://doi.org/10.1007/s00256-004-0792-8Leone A, Costantini AM, Brigida R, et al. Soft-tissue mineralization in Werner syndrome. Skeletal Radiol. 2005;34(1):47-51. doi: https://doi.org/10.1007/s00256-004-0792-8Sickles CK, Gross GP. Progeria (Werner Syndrome). Treasure Island: StatPearls Publishing; 2020.Sickles CK, Gross GP. Progeria (Werner Syndrome). Treasure Island: StatPearls Publishing; 2020.Belaya ZE, Grebennikova TA, Yashina JN, et al. Rare causes of secondary hyperparathyroidism clinical cases of Werner’s syndrome, Gitelman’s syndrome and osteopetrosis among patients referred for primary hyperparathyroidism. In: Osteoporosis International. Vol. 26. London: Springer; 2015. p. 111.Belaya ZE, Grebennikova TA, Yashina JN, et al. Rare causes of secondary hyperparathyroidism clinical cases of Werner’s syndrome, Gitelman’s syndrome and osteopetrosis among patients referred for primary hyperparathyroidism. In: Osteoporosis International. Vol. 26. London: Springer; 2015. p. 111.Lauper JM, Krause A, Vaughan TL, Monnat RJ, Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8(4):e59709. doi: https://doi.org/10.1371/journal.pone.0059709Lauper JM, Krause A, Vaughan TL, Monnat RJ, Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8(4):e59709. doi: https://doi.org/10.1371/journal.pone.0059709de Renty C, Ellis NA. Bloom’s syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. Ageing Res Rev. 2017;33:36-51. doi: https://doi.org/10.1016/j.arr.2016.05.010de Renty C, Ellis NA. Bloom’s syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. Ageing Res Rev. 2017;33:36-51. doi: https://doi.org/10.1016/j.arr.2016.05.010Bloom D. congenital telangiectatic erythema resembling lupus erythematosus in dwarfs<subtitle>Probably a Syndrome Entity. Arch Pediatr Adolesc Med. 1954;88(6):754. doi: https://doi.org/10.1001/archpedi.1954.02050100756008Bloom D. congenital telangiectatic erythema resembling lupus erythematosus in dwarfs<subtitle>Probably a Syndrome Entity. Arch Pediatr Adolesc Med. 1954;88(6):754. doi: https://doi.org/10.1001/archpedi.1954.02050100756008German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28(8):743-753. doi: https://doi.org/10.1002/humu.20501German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28(8):743-753. doi: https://doi.org/10.1002/humu.20501Fares F, Badarneh K, Abosaleh M, et al. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenat Diagn. 2008;28(3):236-241. doi: https://doi.org/10.1002/pd.1943Fares F, Badarneh K, Abosaleh M, et al. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenat Diagn. 2008;28(3):236-241. doi: https://doi.org/10.1002/pd.1943Kaneko H, Kondo N. Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. Expert Rev Mol Diagn. 2004;4(3):393-401. doi: https://doi.org/10.1586/14737159.4.3.393Kaneko H, Kondo N. Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. Expert Rev Mol Diagn. 2004;4(3):393-401. doi: https://doi.org/10.1586/14737159.4.3.393Lu L, Jin W, Wang LL. Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders. Ageing Res Rev. 2017;33:30-35. doi: https://doi.org/10.1016/j.arr.2016.06.002Lu L, Jin W, Wang LL. Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders. Ageing Res Rev. 2017;33:30-35. doi: https://doi.org/10.1016/j.arr.2016.06.002Thomson MS. Poikiloderma Congenitale: Two Cases for Diagnosis. Proc R Soc Med. 1936;29(5):453-455.Thomson MS. Poikiloderma Congenitale: Two Cases for Diagnosis. Proc R Soc Med. 1936;29(5):453-455.Colombo EA, Locatelli A, Cubells Sanchez L, et al. Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome. Int J Mol Sci. 2018;19(4). doi: https://doi.org/10.3390/ijms19041103Colombo EA, Locatelli A, Cubells Sanchez L, et al. Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome. Int J Mol Sci. 2018;19(4). doi: https://doi.org/10.3390/ijms19041103Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev. 2018;173:80-83. doi: https://doi.org/10.1016/j.mad.2018.05.002Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev. 2018;173:80-83. doi: https://doi.org/10.1016/j.mad.2018.05.002Hafsi W, Badri T. Poikiloderma Congenitale. Treasure Island (FL): StatPearls Publishing; 2019.Hafsi W, Badri T. Poikiloderma Congenitale. Treasure Island (FL): StatPearls Publishing; 2019.Araujo SJ, Kuraoka I. Nucleotide excision repair genes shaping embryonic development. Open Biol. 2019;9(10):190166. doi: https://doi.org/10.1098/rsob.190166Araujo SJ, Kuraoka I. Nucleotide excision repair genes shaping embryonic development. Open Biol. 2019;9(10):190166. doi: https://doi.org/10.1098/rsob.190166Spivak G. Nucleotide excision repair in humans. DNA Repair (Amst). 2015;36:13-18. doi: https://doi.org/10.1016/j.dnarep.2015.09.003Spivak G. Nucleotide excision repair in humans. DNA Repair (Amst). 2015;36:13-18. doi: https://doi.org/10.1016/j.dnarep.2015.09.003Moriwaki S, Kanda F, Hayashi M, et al. Xeroderma pigmentosum clinical practice guidelines. J Dermatol. 2017;44(10):1087-1096. doi: https://doi.org/10.1111/1346-8138.13907Moriwaki S, Kanda F, Hayashi M, et al. Xeroderma pigmentosum clinical practice guidelines. J Dermatol. 2017;44(10):1087-1096. doi: https://doi.org/10.1111/1346-8138.13907Brooks BP, Thompson AH, Bishop RJ, et al. Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology. 2013;120(7):1324-1336. doi: https://doi.org/10.1016/j.ophtha.2012.12.044Brooks BP, Thompson AH, Bishop RJ, et al. Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology. 2013;120(7):1324-1336. doi: https://doi.org/10.1016/j.ophtha.2012.12.044Bradford PT, Goldstein AM, Tamura D, et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011;48(3):168-176. doi: https://doi.org/10.1136/jmg.2010.083022Bradford PT, Goldstein AM, Tamura D, et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011;48(3):168-176. doi: https://doi.org/10.1136/jmg.2010.083022Karass M, Naguib MM, Elawabdeh N, et al. Xeroderma pigmentosa: three new cases with an in depth review of the genetic and clinical characteristics of the disease. Fetal Pediatr Pathol. 2015;34(2):120-127. doi: https://doi.org/10.3109/15513815.2014.982336Karass M, Naguib MM, Elawabdeh N, et al. Xeroderma pigmentosa: three new cases with an in depth review of the genetic and clinical characteristics of the disease. Fetal Pediatr Pathol. 2015;34(2):120-127. doi: https://doi.org/10.3109/15513815.2014.982336Kaliki S, Jajapuram SD, Maniar A, Mishra DK. Ocular and Periocular Tumors in Xeroderma Pigmentosum: A Study of 120 Asian Indian Patients. Am J Ophthalmol. 2019;198:146-153. doi: https://doi.org/10.1016/j.ajo.2018.10.011Kaliki S, Jajapuram SD, Maniar A, Mishra DK. Ocular and Periocular Tumors in Xeroderma Pigmentosum: A Study of 120 Asian Indian Patients. Am J Ophthalmol. 2019;198:146-153. doi: https://doi.org/10.1016/j.ajo.2018.10.011Black JO. Xeroderma Pigmentosum. Head Neck Pathol. 2016;10(2):139-144. doi: https://doi.org/10.1007/s12105-016-0707-8Black JO. Xeroderma Pigmentosum. Head Neck Pathol. 2016;10(2):139-144. doi: https://doi.org/10.1007/s12105-016-0707-8Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child. 1936;11(61):1-8. doi: https://doi.org/10.1136/adc.11.61.1Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child. 1936;11(61):1-8. doi: https://doi.org/10.1136/adc.11.61.1Wilson BT, Stark Z, Sutton RE, et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016;18(5):483-493. doi: https://doi.org/10.1038/gim.2015.110Wilson BT, Stark Z, Sutton RE, et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016;18(5):483-493. doi: https://doi.org/10.1038/gim.2015.110Слижов П.А., Долинина Т.И., Плескай Н.М., и др. Маркеры старения в клетках больных синдромом Коккейна. Общие и индивидуальные различия. // Цитология. — 2018. — Т. 60. — №3. — С. 188-199. [Slizhov PA, Dolinina TI, Pleskach NM, et al. Aging markers in cells of patients with Cockayne Syndrome. General and individual differences. Cell and tissue biology. 2018;60(3):188-199. (In Russ.)] doi: https://doi.org/10.31116/tsitol.2018.03.05Слижов П.А., Долинина Т.И., Плескай Н.М., и др. Маркеры старения в клетках больных синдромом Коккейна. Общие и индивидуальные различия. // Цитология. — 2018. — Т. 60. — №3. — С. 188-199. [Slizhov PA, Dolinina TI, Pleskach NM, et al. Aging markers in cells of patients with Cockayne Syndrome. General and individual differences. Cell and tissue biology. 2018;60(3):188-199. (In Russ.)] doi: https://doi.org/10.31116/tsitol.2018.03.05Kubota M, Ohta S, Ando A, et al. Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis. Pediatr Int. 2015;57(3):339-347. doi: https://doi.org/10.1111/ped.12635Kubota M, Ohta S, Ando A, et al. Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis. Pediatr Int. 2015;57(3):339-347. doi: https://doi.org/10.1111/ped.12635Karikkineth AC, Scheibye-Knudsen M, Fivenson E, et al. Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev. 2017;33:3-17. doi: https://doi.org/10.1016/j.arr.2016.08.002Karikkineth AC, Scheibye-Knudsen M, Fivenson E, et al. Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev. 2017;33:3-17. doi: https://doi.org/10.1016/j.arr.2016.08.002Kalantaridou SN, Zoumakis E, Makrigiannakis A, et al. Corticotropin-releasing hormone, stress and human reproduction: an update. J Reprod Immunol. 2010;85(1):33-39. doi: https://doi.org/10.1016/j.jri.2010.02.005Kalantaridou SN, Zoumakis E, Makrigiannakis A, et al. Corticotropin-releasing hormone, stress and human reproduction: an update. J Reprod Immunol. 2010;85(1):33-39. doi: https://doi.org/10.1016/j.jri.2010.02.005Hayashi M, Miwa-Saito N, Tanuma N, Kubota M. Brain vascular changes in Cockayne syndrome. Neuropathology. 2012;32(2):113-117. doi: https://doi.org/10.1111/j.1440-1789.2011.01241.xHayashi M, Miwa-Saito N, Tanuma N, Kubota M. Brain vascular changes in Cockayne syndrome. Neuropathology. 2012;32(2):113-117. doi: https://doi.org/10.1111/j.1440-1789.2011.01241.xKraemer KH, Patronas NJ, Schiffmann R, et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. 2007;145(4):1388-1396. doi: https://doi.org/10.1016/j.neuroscience.2006.12.020Kraemer KH, Patronas NJ, Schiffmann R, et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. 2007;145(4):1388-1396. doi: https://doi.org/10.1016/j.neuroscience.2006.12.020Pereira LB, Valente NYS, Rocha VB. Do you know this syndrome? Ichthyosis associated with neurological condition and alteration of hairs. An Bras Dermatol. 2018;93(1):135-137. doi: https://doi.org/10.1590/abd1806-4841.20187727Pereira LB, Valente NYS, Rocha VB. Do you know this syndrome? Ichthyosis associated with neurological condition and alteration of hairs. An Bras Dermatol. 2018;93(1):135-137. doi: https://doi.org/10.1590/abd1806-4841.20187727Farmaki E, Nedelkopoulou N, Delli F, et al. Brittle Hair, Photosensitivity, Brain Hypomyelination and Immunodeficiency: Clues to Trichothiodystrophy. Indian J Pediatr. 2017;84(1):89-90. doi: https://doi.org/10.1007/s12098-016-2209-9Farmaki E, Nedelkopoulou N, Delli F, et al. Brittle Hair, Photosensitivity, Brain Hypomyelination and Immunodeficiency: Clues to Trichothiodystrophy. Indian J Pediatr. 2017;84(1):89-90. doi: https://doi.org/10.1007/s12098-016-2209-9Potter H, Chial HJ, Caneus J, et al. Chromosome Instability and Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders. Front Genet. 2019;10:1092. doi: https://doi.org/10.3389/fgene.2019.01092Potter H, Chial HJ, Caneus J, et al. Chromosome Instability and Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders. Front Genet. 2019;10:1092. doi: https://doi.org/10.3389/fgene.2019.01092Khetarpal P, Das S, Panigrahi I, Munshi A. Primordial dwarfism: overview of clinical and genetic aspects. Mol Genet Genomics. 2016;291(1):1-15. doi: https://doi.org/10.1007/s00438-015-1110-yKhetarpal P, Das S, Panigrahi I, Munshi A. Primordial dwarfism: overview of clinical and genetic aspects. Mol Genet Genomics. 2016;291(1):1-15. doi: https://doi.org/10.1007/s00438-015-1110-yO’Driscoll M, Ruiz-Perez VL, Woods CG, et al. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33(4):497-501. doi: https://doi.org/10.1038/ng1129O’Driscoll M, Ruiz-Perez VL, Woods CG, et al. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33(4):497-501. doi: https://doi.org/10.1038/ng1129Qvist P, Huertas P, Jimeno S, et al. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310. doi: https://doi.org/10.1371/journal.pgen.1002310Qvist P, Huertas P, Jimeno S, et al. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310. doi: https://doi.org/10.1371/journal.pgen.1002310Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS. Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010;47(6):411-414. doi: https://doi.org/10.1136/jmg.2009.076646Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS. Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010;47(6):411-414. doi: https://doi.org/10.1136/jmg.2009.076646Kalay E, Yigit G, Aslan Y, et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011;43(1):23-26. doi: https://doi.org/10.1038/ng.725Kalay E, Yigit G, Aslan Y, et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011;43(1):23-26. doi: https://doi.org/10.1038/ng.725Sir JH, Barr AR, Nicholas AK, et al. A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011;43(11):1147-1153. doi: https://doi.org/10.1038/ng.971Sir JH, Barr AR, Nicholas AK, et al. A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011;43(11):1147-1153. doi: https://doi.org/10.1038/ng.971Dauber A, Lafranchi SH, Maliga Z, et al. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J Clin Endocrinol Metab. 2012;97(11):E2140-2151. doi: https://doi.org/10.1210/jc.2012-2150Dauber A, Lafranchi SH, Maliga Z, et al. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J Clin Endocrinol Metab. 2012;97(11):E2140-2151. doi: https://doi.org/10.1210/jc.2012-2150Shaheen R, Faqeih E, Ansari S, et al. Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res. 2014;24(2):291-299. doi: https://doi.org/10.1101/gr.160572.113Shaheen R, Faqeih E, Ansari S, et al. Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res. 2014;24(2):291-299. doi: https://doi.org/10.1101/gr.160572.113Ogi T, Walker S, Stiff T, et al. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet. 2012;8(11):e1002945. doi: https://doi.org/10.1371/journal.pgen.1002945Ogi T, Walker S, Stiff T, et al. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet. 2012;8(11):e1002945. doi: https://doi.org/10.1371/journal.pgen.1002945Barbelanne M, Tsang WY. Molecular and cellular basis of autosomal recessive primary microcephaly. Biomed Res Int. 2014;2014:547986. doi: https://doi.org/10.1155/2014/547986Barbelanne M, Tsang WY. Molecular and cellular basis of autosomal recessive primary microcephaly. Biomed Res Int. 2014;2014:547986. doi: https://doi.org/10.1155/2014/547986Savage SA. Dyskeratosis Congenita. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2020.Savage SA. Dyskeratosis Congenita. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2020.Sharma RK, Gupta M, Sood S, Gupta A. Dyskeratosis congenita: presentation of cutaneous triad in a sporadic case. BMJ Case Rep. 2018;11(1). doi: https://doi.org/10.1136/bcr-2018-226736Sharma RK, Gupta M, Sood S, Gupta A. Dyskeratosis congenita: presentation of cutaneous triad in a sporadic case. BMJ Case Rep. 2018;11(1). doi: https://doi.org/10.1136/bcr-2018-226736Aplas V. Poikiloderma, parapsoriasis and atrophia cutis cum pigmentatione, dystrophia ungium et leukoplakia oris Zinsser, so-called dyskeratosis congenita. Arch Klin Exp Dermatol. 1956;202(3):224-237. doi: https://doi.org/10.1007/bf00476707Aplas V. Poikiloderma, parapsoriasis and atrophia cutis cum pigmentatione, dystrophia ungium et leukoplakia oris Zinsser, so-called dyskeratosis congenita. Arch Klin Exp Dermatol. 1956;202(3):224-237. doi: https://doi.org/10.1007/bf00476707Wang F, Du YQ, Gong W, et al. Research progress of dyskeratosis congenita. Zhonghua Kou Qiang Yi Xue Za Zhi. 2019;54(2):130-134. doi: https://doi.org/10.3760/cma.j.issn.1002-0098.2019.02.010Wang F, Du YQ, Gong W, et al. Research progress of dyskeratosis congenita. Zhonghua Kou Qiang Yi Xue Za Zhi. 2019;54(2):130-134. doi: https://doi.org/10.3760/cma.j.issn.1002-0098.2019.02.010Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med. 2010;12(12):753-764. doi: https://doi.org/10.1097/GIM.0b013e3181f415b5Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med. 2010;12(12):753-764. doi: https://doi.org/10.1097/GIM.0b013e3181f415b5Dodson LM, Baldan A, Nissbeck M, et al. From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants. Hum Mutat. 2019;40(12):2414-2429. doi: https://doi.org/10.1002/humu.23898Dodson LM, Baldan A, Nissbeck M, et al. From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants. Hum Mutat. 2019;40(12):2414-2429. doi: https://doi.org/10.1002/humu.23898Savage SA. Beginning at the ends: telomeres and human disease. F1000Res. 2018;7. doi: https://doi.org/10.12688/f1000research.14068.1Savage SA. Beginning at the ends: telomeres and human disease. F1000Res. 2018;7. doi: https://doi.org/10.12688/f1000research.14068.1Kutbay NO, Yurekli BS, Erdemir Z, et al. A case of dyskeratosis congenita associated with hypothyroidism and hypogonadism. Hormones (Athens). 2016;15(2):297-299. doi: https://doi.org/10.14310/horm.2002.1655Kutbay NO, Yurekli BS, Erdemir Z, et al. A case of dyskeratosis congenita associated with hypothyroidism and hypogonadism. Hormones (Athens). 2016;15(2):297-299. doi: https://doi.org/10.14310/horm.2002.1655Shomali W, Brar R. Late presentation of dyskeratosis congenita. Br J Haematol. 2019;187(3):273. doi: https://doi.org/10.1111/bjh.16131Shomali W, Brar R. Late presentation of dyskeratosis congenita. Br J Haematol. 2019;187(3):273. doi: https://doi.org/10.1111/bjh.16131Du H, Guo Y, Ma D, et al. A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. Medicine (Baltimore). 2018;97(19):e0724. doi: https://doi.org/10.1097/MD.0000000000010724Du H, Guo Y, Ma D, et al. A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. Medicine (Baltimore). 2018;97(19):e0724. doi: https://doi.org/10.1097/MD.0000000000010724de Boer J, Andressoo JO, de Wit J, et al. Premature aging in mice deficient in DNA repair and transcription. Science. 2002;296(5571):1276-1279. doi: https://doi.org/10.1126/science.1070174de Boer J, Andressoo JO, de Wit J, et al. Premature aging in mice deficient in DNA repair and transcription. Science. 2002;296(5571):1276-1279. doi: https://doi.org/10.1126/science.1070174Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta. 2007;1775(1):138-162. doi: https://doi.org/10.1016/j.bbcan.2006.08.007Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta. 2007;1775(1):138-162. doi: https://doi.org/10.1016/j.bbcan.2006.08.007Zhang W, Li J, Suzuki K, et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348(6239):1160-1163. doi: https://doi.org/10.1126/science.aaa1356Zhang W, Li J, Suzuki K, et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348(6239):1160-1163. doi: https://doi.org/10.1126/science.aaa1356Shumaker DK, Dechat T, Kohlmaier A, et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A. 2006;103(23):8703-8708. doi: https://doi.org/10.1073/pnas.0602569103Shumaker DK, Dechat T, Kohlmaier A, et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A. 2006;103(23):8703-8708. doi: https://doi.org/10.1073/pnas.0602569103Davis T, Brook AJ, Rokicki MJ, et al. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016;9(2). doi: https://doi.org/10.3390/ph9020023Davis T, Brook AJ, Rokicki MJ, et al. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016;9(2). doi: https://doi.org/10.3390/ph9020023Tivey HS, Brook AJ, Rokicki MJ, et al. p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes. Biogerontology. 2013;14(1):47-62. doi: https://doi.org/10.1007/s10522-012-9407-2Tivey HS, Brook AJ, Rokicki MJ, et al. p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes. Biogerontology. 2013;14(1):47-62. doi: https://doi.org/10.1007/s10522-012-9407-2Bagley MC, Davis T, Murziani PG, et al. Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome. Pharmaceuticals (Basel). 2010;3(6):1842-1872. doi: https://doi.org/10.3390/ph3061842Bagley MC, Davis T, Murziani PG, et al. Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome. Pharmaceuticals (Basel). 2010;3(6):1842-1872. doi: https://doi.org/10.3390/ph3061842Yamaga M, Takemoto M, Shoji M, et al. Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY). 2017;9(7):1738-1744. doi: https://doi.org/10.18632/aging.101265Yamaga M, Takemoto M, Shoji M, et al. Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY). 2017;9(7):1738-1744. doi: https://doi.org/10.18632/aging.101265von Walden F, Liu C, Aurigemma N, Nader GA. mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling. Am J Physiol Cell Physiol. 2016;311(4):C663-C672. doi: https://doi.org/10.1152/ajpcell.00144.2016von Walden F, Liu C, Aurigemma N, Nader GA. mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling. Am J Physiol Cell Physiol. 2016;311(4):C663-C672. doi: https://doi.org/10.1152/ajpcell.00144.2016Dormond O. mTOR in Human Diseases. Int J Mol Sci. 2019;20(9). doi: https://doi.org/10.3390/ijms20092351Dormond O. mTOR in Human Diseases. Int J Mol Sci. 2019;20(9). doi: https://doi.org/10.3390/ijms20092351Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood. 2018;131(5):488-495. doi: https://doi.org/10.1182/blood-2017-07-746396Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood. 2018;131(5):488-495. doi: https://doi.org/10.1182/blood-2017-07-746396Wu D, Prives C. Relevance of the p53-MDM2 axis to aging. Cell Death Differ. 2018;25(1):169-179. doi: https://doi.org/10.1038/cdd.2017.187Wu D, Prives C. Relevance of the p53-MDM2 axis to aging. Cell Death Differ. 2018;25(1):169-179. doi: https://doi.org/10.1038/cdd.2017.187Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005;69(1):79-100. doi: https://doi.org/10.1128/MMBR.69.1.79-100.2005Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005;69(1):79-100. doi: https://doi.org/10.1128/MMBR.69.1.79-100.2005Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127-134. doi: https://doi.org/10.1159/000484629Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127-134. doi: https://doi.org/10.1159/000484629Wiza C, Nascimento EB, Ouwens DM. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am J Physiol Endocrinol Metab. 2012;302(12):E1453-1460. doi: https://doi.org/10.1152/ajpendo.00660.2011Wiza C, Nascimento EB, Ouwens DM. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am J Physiol Endocrinol Metab. 2012;302(12):E1453-1460. doi: https://doi.org/10.1152/ajpendo.00660.2011Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91-99. doi: https://doi.org/10.1016/j.ccr.2004.06.007Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91-99. doi: https://doi.org/10.1016/j.ccr.2004.06.007Mammucari C, Milan G, Romanello V, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458-471. doi: https://doi.org/10.1016/j.cmet.2007.11.001Mammucari C, Milan G, Romanello V, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458-471. doi: https://doi.org/10.1016/j.cmet.2007.11.001Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472-483. doi: https://doi.org/10.1016/j.cmet.2007.11.004Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472-483. doi: https://doi.org/10.1016/j.cmet.2007.11.004Wu JJ, Liu J, Chen EB, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4(5):913-920. doi: https://doi.org/10.1016/j.celrep.2013.07.030Wu JJ, Liu J, Chen EB, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4(5):913-920. doi: https://doi.org/10.1016/j.celrep.2013.07.030Vellai T, Takacs-Vellai K, Zhang Y, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426(6967):620. doi: https://doi.org/10.1038/426620aVellai T, Takacs-Vellai K, Zhang Y, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426(6967):620. doi: https://doi.org/10.1038/426620aBjedov I, Toivonen JM, Kerr F, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35-46. doi: https://doi.org/10.1016/j.cmet.2009.11.010Bjedov I, Toivonen JM, Kerr F, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35-46. doi: https://doi.org/10.1016/j.cmet.2009.11.010Kaeberlein M, Powers RW, 3rd, Steffen KK, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005;310(5751):1193-1196. doi: https://doi.org/10.1126/science.1115535Kaeberlein M, Powers RW, 3rd, Steffen KK, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005;310(5751):1193-1196. doi: https://doi.org/10.1126/science.1115535Seto B. Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. Clin Transl Med. 2012;1(1):29. doi: https://doi.org/10.1186/2001-1326-1-29Seto B. Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. Clin Transl Med. 2012;1(1):29. doi: https://doi.org/10.1186/2001-1326-1-29Demidenko ZN, Zubova SG, Bukreeva EI, et al. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8(12):1888-1895. doi: https://doi.org/10.4161/cc.8.12.8606Demidenko ZN, Zubova SG, Bukreeva EI, et al. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8(12):1888-1895. doi: https://doi.org/10.4161/cc.8.12.8606Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-395. doi: https://doi.org/10.1038/nature08221Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-395. doi: https://doi.org/10.1038/nature08221Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570-578. doi: https://doi.org/10.1056/NEJMoa012437Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570-578. doi: https://doi.org/10.1056/NEJMoa012437Brown RJ, Oral EA, Cochran E, et al. Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. Endocrine. 2018;60(3):479-489. doi: https://doi.org/10.1007/s12020-018-1589-1Brown RJ, Oral EA, Cochran E, et al. Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. Endocrine. 2018;60(3):479-489. doi: https://doi.org/10.1007/s12020-018-1589-1Gordon LB, Kleinman ME, Miller DT, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109(41):16666-16671. doi: https://doi.org/10.1073/pnas.1202529109Gordon LB, Kleinman ME, Miller DT, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109(41):16666-16671. doi: https://doi.org/10.1073/pnas.1202529109Gordon LB, Massaro J, D’Agostino RB, Sr., et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014;130(1):27-34. doi: https://doi.org/10.1161/CIRCULATIONAHA.113.008285Gordon LB, Massaro J, D’Agostino RB, Sr., et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014;130(1):27-34. doi: https://doi.org/10.1161/CIRCULATIONAHA.113.008285Gordon LB, Shappell H, Massaro J, et al. Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018;319(16):1687-1695. doi: https://doi.org/10.1001/jama.2018.3264Gordon LB, Shappell H, Massaro J, et al. Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018;319(16):1687-1695. doi: https://doi.org/10.1001/jama.2018.3264McNally EM, Wyatt EJ. Welcome to the splice age: antisense oligonucleotide-mediated exon skipping gains wider applicability. J Clin Invest. 2016;126(4):1236-1238. doi: https://doi.org/10.1172/JCI86799McNally EM, Wyatt EJ. Welcome to the splice age: antisense oligonucleotide-mediated exon skipping gains wider applicability. J Clin Invest. 2016;126(4):1236-1238. doi: https://doi.org/10.1172/JCI86799Lee JM, Nobumori C, Tu Y, et al. Modulation of LMNA splicing as a strategy to treat prelamin A diseases. J Clin Invest. 2016;126(4):1592-1602. doi: https://doi.org/10.1172/JCI85908Lee JM, Nobumori C, Tu Y, et al. Modulation of LMNA splicing as a strategy to treat prelamin A diseases. J Clin Invest. 2016;126(4):1592-1602. doi: https://doi.org/10.1172/JCI85908Ершова О.Б., Белова К.Ю., Дегтярев А.А., и др. Анализ летальности у пациентов с переломом проксимального отдела бедра. // Остеопороз и остеопатии. — 2015. — Т. 18. — №3. — С. 3-8. [Ershova OB, Belova KY, Degtyarev AA, et al. Analysis of mortality in patients with a fracture of the proximal femur. Osteoporosis and bone diseases. 2015;18(3):3-8. (In Russ.)] doi: https://doi.org/10.14341/osteo201533-8Ершова О.Б., Белова К.Ю., Дегтярев А.А., и др. Анализ летальности у пациентов с переломом проксимального отдела бедра. // Остеопороз и остеопатии. — 2015. — Т. 18. — №3. — С. 3-8. [Ershova OB, Belova KY, Degtyarev AA, et al. Analysis of mortality in patients with a fracture of the proximal femur. Osteoporosis and bone diseases. 2015;18(3):3-8. (In Russ.)] doi: https://doi.org/10.14341/osteo201533-8Мельниченко Г.А., Белая Ж.Е., Рожинская Л.Я., и др. Краткое изложение клинических рекомендаций по диагностике и лечению остеопороза Российской ассоциации эндокринологов. // Остеопороз и остеопатии. — 2016. — Т. 19. — №3. — С. 28-36. [Melnichenko GA, Belaya ZE, Rozhinskaya LY, et al. Summary of clinical guidelines for the diagnosis and treatment of osteoporosis of the Russian association of endocrinologists. Osteoporosis and bone diseases 2016;19(3):28-36. (In Russ.)] doi: https://doi.org/10.14341/osteo2016328-36Мельниченко Г.А., Белая Ж.Е., Рожинская Л.Я., и др. Краткое изложение клинических рекомендаций по диагностике и лечению остеопороза Российской ассоциации эндокринологов. // Остеопороз и остеопатии. — 2016. — Т. 19. — №3. — С. 28-36. [Melnichenko GA, Belaya ZE, Rozhinskaya LY, et al. Summary of clinical guidelines for the diagnosis and treatment of osteoporosis of the Russian association of endocrinologists. Osteoporosis and bone diseases 2016;19(3):28-36. (In Russ.)] doi: https://doi.org/10.14341/osteo2016328-36Белая Ж.Е., Рожинская Л.Я. Витамин D в терапии остеопороза: его роль в комбинации с препаратами для лечения остеопороза, внескелетные эффекты. // Эффективная фармакотерапия. — 2013. — Т. 38. — №2. — С. 14-29. [Belaya ZY, Rozhinskaya LY. Vitamin D in the treatment of osteoporosis: its role in the combination with antiosteoporotic therapy, non-skeletal effects. Effektivnaya farmakoterapiya. 2013;38(2):14-29. (In Russ.)]Белая Ж.Е., Рожинская Л.Я. Витамин D в терапии остеопороза: его роль в комбинации с препаратами для лечения остеопороза, внескелетные эффекты. // Эффективная фармакотерапия. — 2013. — Т. 38. — №2. — С. 14-29. [Belaya ZY, Rozhinskaya LY. Vitamin D in the treatment of osteoporosis: its role in the combination with antiosteoporotic therapy, non-skeletal effects. Effektivnaya farmakoterapiya. 2013;38(2):14-29. (In Russ.)]Geusens PP, Lems WF. Fracture prevention in postmenopausal women with osteoporosis by an annual infusion of zoledronic acid. Ned Tijdschr Geneeskd. 2007;151(26):1445-1448.Geusens PP, Lems WF. Fracture prevention in postmenopausal women with osteoporosis by an annual infusion of zoledronic acid. Ned Tijdschr Geneeskd. 2007;151(26):1445-1448.Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18):1799-1809. doi: https://doi.org/10.1056/NEJMoa074941Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18):1799-1809. doi: https://doi.org/10.1056/NEJMoa074941Cummings SR, Lui LY, Eastell R, Allen IE. Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis. JAMA Intern Med. 2019. doi: https://doi.org/10.1001/jamainternmed.2019.2779Cummings SR, Lui LY, Eastell R, Allen IE. Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis. JAMA Intern Med. 2019. doi: https://doi.org/10.1001/jamainternmed.2019.2779Bliuc D, Tran T, van Geel T, et al. Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study. Osteoporos Int. 2019;30(4):817-828. doi: https://doi.org/10.1007/s00198-018-4806-0Bliuc D, Tran T, van Geel T, et al. Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study. Osteoporos Int. 2019;30(4):817-828. doi: https://doi.org/10.1007/s00198-018-4806-0Lee P, Ng C, Slattery A, et al. Preadmission Bisphosphonate and Mortality in Critically Ill Patients. J Clin Endocrinol Metab. 2016;101(5):1945-1953. doi: https://doi.org/10.1210/jc.2015-3467Lee P, Ng C, Slattery A, et al. Preadmission Bisphosphonate and Mortality in Critically Ill Patients. J Clin Endocrinol Metab. 2016;101(5):1945-1953. doi: https://doi.org/10.1210/jc.2015-3467Bergman J, Nordstrom A, Hommel A, et al. Bisphosphonates and mortality: confounding in observational studies? Osteoporos Int. 2019;30(10):1973-1982. doi: https://doi.org/10.1007/s00198-019-05097-1Bergman J, Nordstrom A, Hommel A, et al. Bisphosphonates and mortality: confounding in observational studies? Osteoporos Int. 2019;30(10):1973-1982. doi: https://doi.org/10.1007/s00198-019-05097-1Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-1065. doi: https://doi.org/10.1016/j.cmet.2016.05.011Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-1065. doi: https://doi.org/10.1016/j.cmet.2016.05.011Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769-2773. doi: https://doi.org/10.4161/cc.7.17.6625Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769-2773. doi: https://doi.org/10.4161/cc.7.17.6625Landman GW, Kleefstra N, van Hateren KJ, et al. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33(2):322-326. doi: https://doi.org/10.2337/dc09-1380Landman GW, Kleefstra N, van Hateren KJ, et al. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33(2):322-326. doi: https://doi.org/10.2337/dc09-1380Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20. doi: https://doi.org/10.1186/1471-2407-11-20Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20. doi: https://doi.org/10.1186/1471-2407-11-20Tseng CH. Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol. 2012;167(3):409-416. doi: https://doi.org/10.1530/EJE-12-0369Tseng CH. Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol. 2012;167(3):409-416. doi: https://doi.org/10.1530/EJE-12-0369Tosca L, Rame C, Chabrolle C, et al. Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells. Reproduction. 2010;139(2):409-418. doi: https://doi.org/10.1530/REP-09-0351Tosca L, Rame C, Chabrolle C, et al. Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells. Reproduction. 2010;139(2):409-418. doi: https://doi.org/10.1530/REP-09-0351Karnevi E, Said K, Andersson R, Rosendahl AH. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer. 2013;13:235. doi: https://doi.org/10.1186/1471-2407-13-235Karnevi E, Said K, Andersson R, Rosendahl AH. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer. 2013;13:235. doi: https://doi.org/10.1186/1471-2407-13-235Zi FM, He JS, Li Y, et al. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015;356(2 Pt B):443-453. doi: https://doi.org/10.1016/j.canlet.2014.09.050Zi FM, He JS, Li Y, et al. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015;356(2 Pt B):443-453. doi: https://doi.org/10.1016/j.canlet.2014.09.050Niehr F, von Euw E, Attar N, et al. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med. 2011;9:76. doi: https://doi.org/10.1186/1479-5876-9-76Niehr F, von Euw E, Attar N, et al. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med. 2011;9:76. doi: https://doi.org/10.1186/1479-5876-9-76Colquhoun AJ, Venier NA, Vandersluis AD, et al. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 2012;15(4):346-352. doi: https://doi.org/10.1038/pcan.2012.16Colquhoun AJ, Venier NA, Vandersluis AD, et al. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 2012;15(4):346-352. doi: https://doi.org/10.1038/pcan.2012.16Li L, Han R, Xiao H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res. 2014;20(10):2714-2726. doi: https://doi.org/10.1158/1078-0432.CCR-13-2613Li L, Han R, Xiao H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res. 2014;20(10):2714-2726. doi: https://doi.org/10.1158/1078-0432.CCR-13-2613Blandino G, Valerio M, Cioce M, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012;3:865. doi: https://doi.org/10.1038/ncomms1859Blandino G, Valerio M, Cioce M, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012;3:865. doi: https://doi.org/10.1038/ncomms1859Xu Y, Lu S. Metformin inhibits esophagus cancer proliferation through upregulation of USP7. Cell Physiol Biochem. 2013;32(5):1178-1186. doi: https://doi.org/10.1159/000354517Xu Y, Lu S. Metformin inhibits esophagus cancer proliferation through upregulation of USP7. Cell Physiol Biochem. 2013;32(5):1178-1186. doi: https://doi.org/10.1159/000354517Algire C, Amrein L, Zakikhani M, et al. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17(2):351-360. doi: https://doi.org/10.1677/erc-09-0252Algire C, Amrein L, Zakikhani M, et al. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17(2):351-360. doi: https://doi.org/10.1677/erc-09-0252Gandini S, Puntoni M, Heckman-Stoddard BM, et al. Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders. Cancer Prev Res (Phila). 2014;7(9):867-885. doi: https://doi.org/10.1158/1940-6207.capr-13-0424Gandini S, Puntoni M, Heckman-Stoddard BM, et al. Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders. Cancer Prev Res (Phila). 2014;7(9):867-885. doi: https://doi.org/10.1158/1940-6207.capr-13-0424Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865. doi: https://doi.org/10.1016/s0140-6736(98)07037-8Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865. doi: https://doi.org/10.1016/s0140-6736(98)07037-8Lautrup S, Caponio D, Cheung H-H, et al. Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases. Biogerontology. 2019;20(3):255-269. doi: https://doi.org/10.1007/s10522-019-09798-2Lautrup S, Caponio D, Cheung H-H, et al. Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases. Biogerontology. 2019;20(3):255-269. doi: https://doi.org/10.1007/s10522-019-09798-2

The authors declare that there are no conflicts of interest present.