How to Reinvent your Health - by Gary Mark Levin

Peter Attia gives a holistic overview of why our health care is so broken. In the past decade, social determinants of health have become a part of the health record. This is a measure of societal impact on your life. Attia has noted when he travels the difference in societal stress from America. America ranks #35 in terms of our overall health, and #55 in terms of life expectancy.

Societal issues such as work/life balance, cooking more at home, eating out less (processed foods), and walking more, as seen in Europe all contribute to life expectancy.

One good measurement of health is longevity. The United States is not a winner in that regard. The only category we are number one in is our expense. From 1980 to 2019, Commonwealth Fund found that the U.S. spent nearly 17 percent on health care as a percentage of its gross domestic product (GDP). Other countries, like Switzerland, the U.K., Australia, Norway, and more, spent well below that but still earned higher healthcare performance scores. The forecast is not good. Our life expectancy is decreasing, and this was true pre-COVID.

Life expectancy has dropped: Why it matters

This chart is for the overall life expectancy for Americans, however, there are large deviations for some demographics.

Here are the states with the largest declines in life expectancy

The U.S. fares significantly worse than other developed countries, with the Commonwealth Fund finding Japan has an average life expectancy of 84.4 years, Spain and Switzerland at 84 years and Canada averaging 82.3 years.

The chart below is another view.

African Americans have consistently lagged in life expectancy although the gap is closing.

Economic Growth and Life Expectancy – Do Wealthier Countries Live Longer?

There are many determinants of longevity, and do not always correlate with income, or race. Nutrition and lifestyle are important as well.

Health expenditure as a percentage of gross domestic product (GDP) in selected countries

Prevention

Certain diseases can be detected, however, no one test detects early disease.

Breast Cancer, Cervical Cancer, Colon Cancer, and Prostate Cancer can be detected early.

Mental health issues are significant factors, depression, suicide, and risky behavior all contribute to premature death. There is little doubt smallpox, poliovirus and measles have been eliminated which has increased longevity in the past century.

There are many things in action that can contribute to improved quality of life and life expectation.

During the past decade, we have progressed from Health 2.0 and Health 3.0. Today we have entered Health 4.0. Despite rapid technological advances such as remote monitoring, electronic health records, and fewer uninsured our life expectancy has decreased. Peter Attia seems to have put all of it together and I hope my article can disseminate his words and a few of my own.

Medical 4.0 is the fourth medical revolution, employing emerging technologies to create significant advancements in healthcare. New medical 4.0 technology has advanced significantly, ranging from mobile computing to cloud computing, over the previous decade and is now ready to be employed as a commercially accessible, networked system. Such things as virtual reality, artificial intelligence, networked hospitals and medical clinics create huge data banks for analysis.

References:

Outlive, The Science and Art of Longevity (Peter Attia)

Amazon Books about Longevity

Measuring biological aging in humans: A quest Aging Cell. 2020 Feb; 19(2): e13080.Published online 2019 Dec 12. doi: 10.1111/acel.13080

Acosta, J. C. , Banito, A. , Wuestefeld, T. , Georgilis, A. , Janich, P. , Morton, J. P. , … Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology, 15(8), 978–990. 10.1038/ncb2784 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Agarwal, B. , & Baur, J. A. (2011). Resveratrol and life extension. Annals of the New York Academy of Sciences, 1215, 138–143. 10.1111/j.1749-6632.2010.05850.x [PubMed] [CrossRef] [Google Scholar]

Ahmadbeigi, N. , Soleimani, M. , Vasei, M. , Gheisari, Y. , Mortazavi, Y. , Azadmanesh, K. , … Nardi, N. B. (2013). Isolation, characterization, and transplantation of bone marrow‐derived cell components with hematopoietic stem cell niche properties. Stem Cells and Development, 22(23), 3052–3061. 10.1089/scd.2013.0005 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Al Shahrani, M. , Heales, S. , Hargreaves, I. , & Orford, M. (2017). Oxidative stress: Mechanistic insights into inherited mitochondrial disorders and Parkinson’s disease. Journal of Clinical Medicine, 6(11), 100 10.3390/jcm6110100 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Allsopp, R. C. , Vaziri, H. , Patterson, C. , Goldstein, S. , Younglai, E. V. , Futcher, A. B. , … Harley, C. B. (1992). Telomere length predicts replicative capacity of human fibroblasts. Proceedings of the National Academy of Sciences, 89(21), 10114–10118. 10.1073/pnas.89.21.10114 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Anderson, R. M. , Le Couteur, D. G. , & de Cabo, R. (2017). Caloric restriction research: New perspectives on the biology of aging. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 73(1), 1–3. 10.1093/gerona/glx212 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Andreux, P. A. , Blanco‐Bose, W. , Ryu, D. , Burdet, F. , Ibberson, M. , Aebischer, P. , … Rinsch, C. (2019). The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nature Metabolism, 1(6), 595–603. 10.1038/s42255-019-0073-4 [CrossRef] [Google Scholar]

Andriani, G. A. , Almeida, V. P. , Faggioli, F. , Mauro, M. , Tsai, W. L. , Santambrogio, L. , … Montagna, C. (2016). Whole chromosome instability induces senescence and promotes SASP. Scientific Reports, 6(1), 35218 10.1038/srep35218 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Angelini, F. , Pagano, F. , Bordin, A. , Picchio, V. , De Falco, E. , & Chimenti, I. (2017). Getting old through the blood: Circulating molecules in aging and senescence of cardiovascular regenerative cells. Frontiers in Cardiovascular Medicine, 4, 62 10.3389/fcvm.2017.00062 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Arai, Y. , Martin‐Ruiz, C. M. , Takayama, M. , Abe, Y. , Takebayashi, T. , Koyasu, S. , … von Zglinicki, T. (2015). Inflammation, but not telomere length, predicts successful ageing at extreme old age: A longitudinal study of semi‐supercentenarians. EBioMedicine, 2(10), 1549–1558. 10.1016/j.ebiom.2015.07.029 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Arriola Apelo, S. I. , & Lamming, D. W. (2016). Rapamycin: An InhibiTOR of aging emerges from the soil of Easter Island. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 71(7), 841–849. 10.1093/gerona/glw090 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Avin, B. A. , Umbricht, C. B. , & Zeiger, M. A. (2016). Human telomerase reverse transcriptase regulation by DNA methylation, transcription factor binding and alternative splicing (Review). International Journal of Oncology, 49(6), 2199–2205. 10.3892/ijo.2016.3743 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Bae, T. , Tomasini, L. , Mariani, J. , Zhou, B. , Roychowdhury, T. , Franjic, D. , … Vaccarino, F. M. (2017). Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science, 359(6375), 550–555. 10.1126/science.aan8690 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Baker, D. J. , & Petersen, R. C. (2018). Cellular senescence in brain aging and neurodegenerative diseases: Evidence and perspectives. Journal of Clinical Investigation, 128(4), 1208–1216. 10.1172/jci95145 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Baragetti, A. , Palmen, J. , Garlaschelli, K. , Grigore, L. , Humphries, S. , Catapano, A. L. , … Giuseppe Danilo, N. (2016). Leukocyte telomere length, genetically determined, is causally associated with the progression of carotid Intima‐Media Thickness and incidence of cardiovascular events. Atherosclerosis, 252, e252 10.1016/j.atherosclerosis.2016.07.064 [CrossRef] [Google Scholar]

Barker, D. J. P. , Osmond, C. , Winter, P. D. , Margetts, B. , & Simmonds, S. J. (1989). Weight in infancy and death from ischaemic heart disease. The Lancet, 334(8663), 577–580. 10.1016/s0140-6736(89)90710-1 [PubMed] [CrossRef] [Google Scholar]

Batsis, J. A. , Mackenzie, T. A. , Vasquez, E. , Germain, C. M. , Emeny, R. T. , Rippberger, P. , … Bartels, S. J. (2017). Association of adiposity, telomere length and mortality: Data from the NHANES 1999–2002. International Journal of Obesity, 42(2), 198–204. 10.1038/ijo.2017.202 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Beerman, I. (2017). Accumulation of DNA damage in the aged hematopoietic stem cell compartment. Seminars in Hematology, 54(1), 12–18. 10.1053/j.seminhematol.2016.11.001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Behrens, Y. L. , Thomay, K. , Hagedorn, M. , Ebersold, J. , Henrich, L. , Nustede, R. , … Göhring, G. (2017). Comparison of different methods for telomere length measurement in whole blood and blood cell subsets: Recommendations for telomere length measurement in hematological diseases. Genes, Chromosomes and Cancer, 56(9), 700–708. 10.1002/gcc.22475 [PubMed] [CrossRef] [Google Scholar]

Bektas, A. , Schurman, S. H. , Sen, R. , & Ferrucci, L. (2018). Aging, inflammation and the environment. Experimental Gerontology, 105, 10–18. 10.1016/j.exger.2017.12.015 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ben‐Shlomo, Y. , Cooper, R. , & Kuh, D. (2016). The last two decades of life course epidemiology, and its relevance for research on ageing. International Journal of Epidemiology, 45(4), 973–988. 10.1093/ije/dyw096 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Berglund, K. , Reynolds, C. A. , Ploner, A. , Gerritsen, L. , Hovatta, I. , Pedersen, N. L. , & Hägg, S. (2016). Longitudinal decline of leukocyte telomere length in old age and the association with sex and genetic risk. Aging, 8(7), 1398–1415. 10.18632/aging.100995 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Berwick, M. , & Vineis, P. (2005). Measuring DNA repair capacity: Small steps. Journal of the National Cancer Institute, 97(2), 84–85. 10.1093/jnci/dji038 [PubMed] [CrossRef] [Google Scholar]

Bhat, R. , Crowe, E. P. , Bitto, A. , Moh, M. , Katsetos, C. D. , Garcia, F. U. , … Torres, C. (2012). Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE, 7(9), e45069 10.1371/journal.pone.0045069 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Biran, A. , Zada, L. , Abou Karam, P. , Vadai, E. , Roitman, L. , Ovadya, Y. , … Krizhanovsky, V. (2017). Quantitative identification of senescent cells in aging and disease. Aging Cell, 16(4), 661–671. 10.1111/acel.12592 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Bischoff, C. , Petersen, H. C. , Graakjaer, J. , Andersen‐Ranberg, K. , Vaupel, J. W. , Bohr, V. A. , … Christensen, K. (2006). No association between telomere length and survival among the elderly and oldest old. Epidemiology, 17(2), 190–194. 10.1097/01.ede.0000199436.55248.10 [PubMed] [CrossRef] [Google Scholar]

Bjedov, I. , Toivonen, J. M. , Kerr, F. , Slack, C. , Jacobson, J. , Foley, A. , & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster . Cell Metabolism, 11(1), 35–46. 10.1016/j.cmet.2009.11.010 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Blekhman, R. , Man, O. , Herrmann, L. , Boyko, A. R. , Indap, A. , Kosiol, C. , … Przeworski, M. (2008). Natural selection on genes that underlie human disease susceptibility. Current Biology, 18(12), 883–889. 10.1016/j.cub.2008.04.074 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Boccardi, V. , Pelini, L. , Ercolani, S. , Ruggiero, C. , & Mecocci, P. (2015). From cellular senescence to Alzheimer’s disease: The role of telomere shortening. Ageing Research Reviews, 22, 1–8. 10.1016/j.arr.2015.04.003 [PubMed] [CrossRef] [Google Scholar]

Branco, M. R. , Ficz, G. , & Reik, W. (2012). Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Reviews Genetics, 13(1), 7–13. 10.1038/nrg3080 [PubMed] [CrossRef] [Google Scholar]

Bu, H. , Wedel, S. , Cavinato, M. , & Jansen‐Dürr, P. (2017). MicroRNA regulation of oxidative stress‐induced cellular senescence. Oxidative Medicine and Cellular Longevity, 2017, 1–12. 10.1155/2017/2398696 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Bygren, L. , Tinghög, P. , Carstensen, J. , Edvinsson, S. , Kaati, G. , Pembrey, M. E. , & Sjöström, M. (2014). Change in paternal grandmothers' early food supply influenced cardiovascular mortality of the female grandchildren. BMC Genetics, 15(1), 12 10.1186/1471-2156-15-12 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Capri, M. , Moreno‐Villanueva, M. , Cevenini, E. , Pini, E. , Scurti, M. , Borelli, V. , … Franceschi, C. (2015). MARK‐AGE population: From the human model to new insights. Mechanisms of Ageing and Development, 151, 13–17. 10.1016/j.mad.2015.03.010 [PubMed] [CrossRef] [Google Scholar]

Cesari, M. , Pérez‐Zepeda, M. U. , & Marzetti, E. (2017). Frailty and multimorbidity: Different ways of thinking about geriatrics. Journal of the American Medical Directors Association, 18(4), 361–364. 10.1016/j.jamda.2016.12.086 [PubMed] [CrossRef] [Google Scholar]

Chang, J. , Wang, Y. , Shao, L. , Laberge, R.‐M. , Demaria, M. , Campisi, J. , … Zhou, D. (2015). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine, 22(1), 78–83. 10.1038/nm.4010 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Chen, B. H. , Marioni, R. E. , Colicino, E. , Peters, M. J. , Ward‐Caviness, C. K. , Tsai, P. C. , … Horvath, S. (2016). DNA methylation‐based measures of biological age: Meta‐analysis predicting time to death. Aging (Albany NY), 8(9), 1844–1865. 10.18632/aging.101020 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Chen, M. Z. , Moily, N. S. , Bridgford, J. L. , Wood, R. J. , Radwan, M. , Smith, T. A. , … Hatters, D. M. (2017). A thiol probe for measuring unfolded protein load and proteostasis in cells. Nature Communications, 8(1), 474 10.1038/s41467-017-00203-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Chi, M.‐S. , Lee, C.‐Y. , Huang, S.‐C. , Yang, K.‐L. , Ko, H.‐L. , Chen, Y.‐K. , … Chi, K.‐H. (2015). Double autophagy modulators reduce 2‐deoxyglucose uptake in sarcoma patients. Oncotarget, 6(30), 29808–29817. 10.18632/oncotarget.5060 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Childs, B. G. , Durik, M. , Baker, D. J. , & van Deursen, J. M. (2015). Cellular senescence in aging and age‐related disease: From mechanisms to therapy. Nature Medicine, 21(12), 1424–1435. 10.1038/nm.4000 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Childs, B. G. , Gluscevic, M. , Baker, D. J. , Laberge, R.‐M. , Marquess, D. , Dananberg, J. , & van Deursen, J. M. (2017). Senescent cells: An emerging target for diseases of ageing. Nature Reviews Drug Discovery, 16(10), 718–735. 10.1038/nrd.2017.116 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Childs, B. G. , Li, H. , & van Deursen, J. M. (2018). Senescent cells: A therapeutic target for cardiovascular disease. Journal of Clinical Investigation, 128(4), 1217–1228. 10.1172/jci95146 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Choi, J.‐H. , Kim, S.‐Y. , Kim, S.‐K. , Kemp, M. G. , & Sancar, A. (2015). An integrated approach for analysis of the DNA damage response in mammalian cells. Journal of Biological Chemistry, 290(48), 28812–28821. 10.1074/jbc.m115.690354 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Choi, S. , Reiter, D. A. , Shardell, M. , Simonsick, E. M. , Studenski, S. , Spencer, R. G. , … Ferrucci, L. (2016). 31P Magnetic Resonance Spectroscopy assessment of muscle bioenergetics as a predictor of gait speed in the Baltimore longitudinal study of aging. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 71(12), 1638–1645. 10.1093/gerona/glw059 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Coen, P. M. , Jubrias, S. A. , Distefano, G. , Amati, F. , Mackey, D. C. , Glynn, N. W. , … Goodpaster, B. H. (2012). Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. The Journals of Gerontology: Series A, 68(4), 447–455. 10.1093/gerona/gls196 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Coggan, A. R. (1995). Muscle biopsy as a tool in the study of aging. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 50, 30–34. [PubMed] [Google Scholar]

Cohen, A. , Morissette‐Thomas, V. , Ferrucci, L. , & Fried, L. (2016). Deep biomarkers of aging are population‐dependent. Aging, 8(9), 2253–2255. 10.18632/aging.101034 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Collins, A. R. (2014). Measuring oxidative damage to DNA and its repair with the comet assay. Biochimica Et Biophysica Acta (BBA) ‐ General Subjects, 1840(2), 794–800. 10.1016/j.bbagen.2013.04.022 [PubMed] [CrossRef] [Google Scholar]

Colquitt, B. M. , Allen, W. E. , Barnea, G. , & Lomvardas, S. (2013). Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity. Proceedings of the National Academy of Sciences, 110(36), 14682–14687. 10.1073/pnas.1302759110 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Consolini, A. E. , Ragone, M. I. , Bonazzola, P. , & Colareda, G. A. (2017). Mitochondrial Bioenergetics During Ischemia and Reperfusion. Adv Exp Med Biol, 982, 141–167. 10.1007/978-3-319-55330-6_8 [PubMed] [CrossRef] [Google Scholar]

Coppé, J.‐P. , Desprez, P.‐Y. , Krtolica, A. , & Campisi, J. (2010). The senescence‐associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease, 5(1), 99–118. 10.1146/annurev-pathol-121808-102144 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Cuervo, A. M. , Bergamini, E. , Brunk, U. T. , Dröge, W. , Ffrench, M. , & Terman, A. (2005). Autophagy and aging: The importance of maintaining "Clean" cells. Autophagy, 1(3), 131–140. 10.4161/auto.1.3.2017 [PubMed] [CrossRef] [Google Scholar]

Cuervo, A. M. , & Macian, F. (2014). Autophagy and the immune function in aging. Current Opinion in Immunology, 29, 97–104. 10.1016/j.coi.2014.05.006 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Cuervo, A. M. , Wong, E. S. P. , & Martinez‐Vicente, M. (2010). Protein degradation, aggregation, and misfolding. Movement Disorders, 25(S1), S49–S54. 10.1002/mds.22718 [PubMed] [CrossRef] [Google Scholar]

de Haan, G. , & Lazare, S. S. (2017). Aging of hematopoietic stem cells. Blood, 131(5), 479–487. 10.1182/blood-2017-06-746412 [PubMed] [CrossRef] [Google Scholar]

Degerman, S. , Josefsson, M. , Nordin Adolfsson, A. , Wennstedt, S. , Landfors, M. , Haider, Z. , … Adolfsson, R. (2017). Maintained memory in aging is associated with young epigenetic age. Neurobiology of Aging, 55, 167–171. 10.1016/j.neurobiolaging.2017.02.009 [PubMed] [CrossRef] [Google Scholar]

Dexheimer, V. , Mueller, S. , Braatz, F. , & Richter, W. (2011). Reduced reactivation from dormancy but maintained lineage choice of human mesenchymal stem cells with donor age. PLoS ONE, 6(8), e22980 10.1371/journal.pone.0022980 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Diekman, B. O. , Sessions, G. A. , Collins, J. A. , Knecht, A. K. , Strum, S. L. , Mitin, N. K. , … Sharpless, N. E. (2018). Expression of p16INK 4a is a biomarker of chondrocyte aging but does not cause osteoarthritis. Aging Cell, 17(4), e12771 10.1111/acel.12771 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Dikalov, S. I. , & Harrison, D. G. (2014). Methods for detection of mitochondrial and cellular reactive oxygen species. Antioxidants & Redox Signaling, 20(2), 372–382. 10.1089/ars.2012.4886 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ding, J. , Sidore, C. , Butler, T. J. , Wing, M. K. , Qian, Y. , Meirelles, O. , … Schlessinger, D. (2015). Assessing mitochondrial DNA variation and copy number in lymphocytes of ~2,000 Sardinians using tailored sequencing analysis tools. PLoS Genetics, 11(7), e1005306 10.1371/journal.pgen.1005306 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Eerola, J. , Kananen, L. , Manninen, K. , Hellstrom, O. , Tienari, P. J. , & Hovatta, I. (2010). No evidence for shorter leukocyte telomere length in Parkinson's disease patients. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 65A(11), 1181–1184. 10.1093/gerona/glq125 [PubMed] [CrossRef] [Google Scholar]

Eichler, F. , Duncan, C. , Musolino, P. L. , Orchard, P. J. , De Oliveira, S. , Thrasher, A. J. , … Williams, D. A. (2017). Hematopoietic stem‐cell gene therapy for cerebral adrenoleukodystrophy. New England Journal of Medicine, 377(17), 1630–1638. 10.1056/nejmoa1700554 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Eirin, A. , Saad, A. , Tang, H. , Herrmann, S. M. , Woollard, J. R. , Lerman, A. , … Lerman, L. O. (2016). Urinary mitochondrial DNA copy number identifies chronic renal injury in hypertensive patients. Hypertension, 68(2), 401–410. 10.1161/hypertensionaha.116.07849 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Eisenberg, T. , Knauer, H. , Schauer, A. , Buttner, S. , Ruckenstuhl, C. , Carmona‐Gutierrez, D. , … Madeo, F. (2009). Induction of autophagy by spermidine promotes longevity. Nature Cell Biology, 11(11), 1305–1314. 10.1038/ncb1975 [PubMed] [CrossRef] [Google Scholar]

El‐Chemaly, S. , Cheung, F. , Kotliarov, Y. , O’Brien, K. J. , Gahl, W. A. , Chen, J. , … Gochuico, B. R. (2018). The immunome in two inherited forms of pulmonary fibrosis. Frontiers in Immunology, 9, 76 10.3389/fimmu.2018.00076 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

El‐Chemaly, S. , Taveira‐Dasilva, A. , Goldberg, H. J. , Peters, E. , Haughey, M. , Bienfang, D. , … Henske, E. P. (2017). Sirolimus and autophagy inhibition in lymphangioleiomyomatosis. Chest, 151(6), 1302–1310. 10.1016/j.chest.2017.01.033 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

El‐Zein, R. A. , Monroy, C. M. , Cortes, A. , Spitz, M. R. , Greisinger, A. , & Etzel, C. J. (2010). Rapid method for determination of DNA repair capacity in human peripheral blood lymphocytes amongst smokers. BMC Cancer, 10(1), 439 10.1186/1471-2407-10-439 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Epel, E. S. , Blackburn, E. H. , Lin, J. , Dhabhar, F. S. , Adler, N. E. , Morrow, J. D. , & Cawthon, R. M. (2004). Accelerated telomere shortening in response to life stress. Proceedings of the National Academy of Sciences, 101(49), 17312–17315. 10.1073/pnas.0407162101 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Evangelou, K. , Lougiakis, N. , Rizou, S. V. , Kotsinas, A. , Kletsas, D. , Muñoz‐Espín, D. , … Gorgoulis, V. G. (2016). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell, 16(1), 192–197. 10.1111/acel.12545 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Fabbri, E. , An, Y. , Zoli, M. , Simonsick, E. M. , Guralnik, J. M. , Bandinelli, S. , … Ferrucci, L. (2014). Aging and the burden of multimorbidity: Associations with inflammatory and anabolic hormonal biomarkers. The Journals of Gerontology: Series A, 70(1), 63–70. 10.1093/gerona/glu127 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Fabbri, E. , Chia, C. W. , Spencer, R. G. , Fishbein, K. W. , Reiter, D. A. , Cameron, D. , … Ferrucci, L. (2016). Insulin resistance is associated with reduced mitochondrial oxidative capacity measured by 31P‐magnetic resonance spectroscopy in participants without diabetes from the Baltimore longitudinal study of aging. Diabetes, 66(1), 170–176. 10.2337/db16-0754 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Fabbri, E. , Zoli, M. , Gonzalez‐Freire, M. , Salive, M. E. , Studenski, S. A. , & Ferrucci, L. (2015). Aging and multimorbidity: New tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association, 16(8), 640–647. 10.1016/j.jamda.2015.03.013 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Fan, M. , Chen, W. , Liu, W. , Du, G.‐Q. , Jiang, S.‐L. , Tian, W.‐C. , … Tian, H. (2010). The effect of age on the efficacy of human mesenchymal stem cell transplantation after a myocardial infarction. Rejuvenation Research, 13(4), 429–438. 10.1089/rej.2009.0986 [PubMed] [CrossRef] [Google Scholar]

Fang, L. , Neutzner, A. , Turtschi, S. , Flammer, J. , & Mozaffarieh, M. (2015). Comet Assay as an indirect measure of systemic oxidative stress. Journal of Visualized Experiments, 99, e52763 10.3791/52763 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ferrucci, L. , Corsi, A. , Lauretani, F. , Bandinelli, S. , Bartali, B. , Taub, D. D. , … Longo, D. L. (2005). The origins of age‐related proinflammatory state. Blood, 105(6), 2294–2299. 10.1182/blood-2004-07-2599 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ferrucci, L. , & Fabbri, E. (2018). Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology, 15(9), 505–522. 10.1038/s41569-018-0064-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ferrucci, L. , Harris, T. B. , Guralnik, J. M. , Tracy, R. P. , Corti, M.‐C. , Cohen, H. J. , … Havlik, R. J. (1999). Serum IL‐6 level and the development of disability in older persons. Journal of the American Geriatrics Society, 47(6), 639–646. 10.1111/j.1532-5415.1999.tb01583.x [PubMed] [CrossRef] [Google Scholar]

Ferrucci, L. , Levine, M. E. , Kuo, P. L. , & Simonsick, E. M. (2018). Time and the metrics of aging. Circulation Research, 123(7), 740–744. 10.1161/CIRCRESAHA.118.312816 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Ferrucci, L. , Penninx, B. W. J. H. , Volpato, S. , Harris, T. B. , Bandeen‐Roche, K. , Balfour, J. , … Md, J. M. G. (2002). Change in muscle strength explains accelerated decline of physical function in older women with high interleukin‐6 serum levels. Journal of the American Geriatrics Society, 50(12), 1947–1954. 10.1046/j.1532-5415.2002.50605.x [PubMed] [CrossRef] [Google Scholar]

Franceschi, C. , & Campisi, J. (2014). Chronic inflammation (Inflammaging) and its potential contribution to age‐associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl. 1), S4–S9. 10.1093/gerona/glu057 [PubMed] [CrossRef] [Google Scholar]

Franco, I. , Johansson, A. , Olsson, K. , Vrtačnik, P. , Lundin, P. , Helgadottir, H. T. , … Eriksson, M. (2018). Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nature Communications, 9(1), 800 10.1038/s41467-018-03244-6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Friedman, E. M. , Christ, S. L. , & Mroczek, D. K. (2015). Inflammation partially mediates the association of multimorbidity and functional limitations in a national sample of middle‐aged and older adults. Journal of Aging and Health, 27(5), 843–863. 10.1177/0898264315569453 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Fulop, T. , Larbi, A. , Dupuis, G. , Le Page, A. , Frost, E. H. , Cohen, A. A. , … Franceschi, C. (2018). Immunosenescence and inflamm‐aging as two sides of the same coin: Friends or foes? Frontiers in Immunology, 8, 1960 10.3389/fimmu.2017.01960 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Gale, C. R. , Marioni, R. E. , Čukić, I. , Chastin, S. F. , Dall, P. M. , Dontje, M. L. , … Deary, I. J. (2018). The epigenetic clock and objectively measured sedentary and walking behavior in older adults: The Lothian Birth Cohort 1936. Clinical Epigenetics, 10(1), 4 10.1186/s13148-017-0438-z [PMC free article] [PubMed] [CrossRef] [Google Scholar]

García‐Calzón, S. , Gea, A. , Razquin, C. , Corella, D. , Lamuela‐Raventós, R. M. , Martínez, J. A. , … Marti, A. (2013). Longitudinal association of telomere length and obesity indices in an intervention study with a Mediterranean diet: The PREDIMED‐NAVARRA trial. International Journal of Obesity, 38(2), 177–182. 10.1038/ijo.2013.68 [PubMed] [CrossRef] [Google Scholar]

García‐Prat, L. , Martínez‐Vicente, M. , Perdiguero, E. , Ortet, L. , Rodríguez‐Ubreva, J. , Rebollo, E. , … Muñoz‐Cánoves, P. (2016). Autophagy maintains stemness by preventing senescence. Nature, 529(7584), 37–42. 10.1038/nature16187 [PubMed] [CrossRef] [Google Scholar]

Gensous, N. , Bacalini, M. G. , Pirazzini, C. , Marasco, E. , Giuliani, C. , Ravaioli, F. , … Garagnani, P. (2017). The epigenetic landscape of age‐related diseases: The geroscience perspective. Biogerontology, 18(4), 549–559. 10.1007/s10522-017-9695-7 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators . (2016). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053), 1545–1602. 10.1016/s0140-6736(16)31678-6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Godderis, L. , Schouteden, C. , Tabish, A. , Poels, K. , Hoet, P. , Baccarelli, A. A. , & Van Landuyt, K. (2015). Global methylation and hydroxymethylation in DNA from blood and saliva in healthy volunteers. BioMed Research International, 2015, 845041 10.1155/2015/845041 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Goglin, S. E. , Farzaneh‐Far, R. , Epel, E. S. , Lin, J. , Blackburn, E. H. , & Whooley, M. A. (2016). Correction: Change in leukocyte telomere length predicts mortality in patients with stable coronary heart disease from the heart and soul study. PLoS ONE, 11(12), e0168868 10.1371/journal.pone.0168868 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Golpanian, S. , DiFede, D. L. , Khan, A. , Schulman, I. H. , Landin, A. M. , Tompkins, B. A. , … Hare, J. M. (2017). Allogeneic human mesenchymal stem cell infusions for aging frailty. The Journals of Gerontology: Series A, 72(11), 1505–1512. 10.1093/gerona/glx056 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Golpanian, S. , DiFede, D. L. , Pujol, M. V. , Lowery, M. H. , Levis‐Dusseau, S. , Goldstein, B. J. , … Hare, J. M. (2016). Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget, 7(11), 11899–11912. 10.18632/oncotarget.7727 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Gonzales‐Ebsen, A. C. , Gregersen, N. , & Olsen, R. K. (2017). Linking telomere loss and mitochondrial dysfunction in chronic disease. Frontiers in Bioscience (Landmark Ed), 22, 117–127. [PubMed] [Google Scholar]

Gonzalez‐Freire, M. , de Cabo, R. , Bernier, M. , Sollott, S. J. , Fabbri, E. , Navas, P. , & Ferrucci, L. (2015). Reconsidering the role of mitochondria in aging. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 70, 1334–1342. [PMC free article] [PubMed] [Google Scholar]

Gonzalez‐Freire, M. , Scalzo, P. , D'Agostino, J. , Moore, Z. A. , Diaz‐Ruiz, A. , Fabbri, E. , … Ferrucci, L. (2018). Skeletal muscle ex vivo mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness, and muscle strength: The Baltimore Longitudinal Study of Aging. Aging Cell, 17(2), e12725 10.1111/acel.12725 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Greider, C. W. (1998). Telomeres and senescence: The history, the experiment, the future. Current Biology, 8(5), R178–R181. 10.1016/s0960-9822(98)70105-8 [PubMed] [CrossRef] [Google Scholar]

Greider, C. W. (2010). Telomerase discovery: The excitement of putting together pieces of the puzzle (nobel lecture). Angewandte Chemie International Edition, 49(41), 7422–7439. 10.1002/anie.201002408 [PubMed] [CrossRef] [Google Scholar]

Guiding Principles for the Care of Older Adults with Multimorbidity: An Approach for Clinicians . (2012). Guiding principles for the care of older adults with multimorbidity: An approach for clinicians: American Geriatrics Society Expert Panel on the Care of Older Adults with Multimorbidity. Journal of the American Geriatrics Society, 60(10), E1–E25. 10.1111/j.1532-5415.2012.04188.x [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Gupta, V. K. , Scheunemann, L. , Eisenberg, T. , Mertel, S. , Bhukel, A. , Koemans, T. S. , … Sigrist, S. J. (2013). Restoring polyamines protects from age‐induced memory impairment in an autophagy‐dependent manner. Nature Neuroscience, 16(10), 1453–1460. 10.1038/nn.3512 [PubMed] [CrossRef] [Google Scholar]

Haferkamp, S. , Scurr, L. L. , Becker, T. M. , Frausto, M. , Kefford, R. F. , & Rizos, H. (2009). Oncogene‐induced senescence does not require the p16INK4a or p14ARF melanoma tumor suppressors. Journal of Investigative Dermatology, 129(8), 1983–1991. 10.1038/jid.2009.5 [PubMed] [CrossRef] [Google Scholar]

Hall, B. M. , Balan, V. , Gleiberman, A. S. , Strom, E. , Krasnov, P. , Virtuoso, L. P. , … Gudkov, A. V. (2017). p16(Ink4a) and senescence‐associated β‐galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging, 9(8), 1867–1884. 10.18632/aging.101268 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hamann, I. , & Hartwig, A. (2014). Quantification of DNA repair capacity towards oxidatively damaged DNA in subcellular and cellular systems by a nonradioactive cleavage assay. Methods Mol Biol, 1208, 73–84. 10.1007/978-1-4939-1441-8_6 [PubMed] [CrossRef] [Google Scholar]

Hammadah, M. , Al Mheid, I. , Wilmot, K. , Ramadan, R. , Abdelhadi, N. , Alkhoder, A. , … Vaccarino, V. (2017). Telomere shortening, regenerative capacity, and cardiovascular outcomes. Circulation Research, 120(7), 1130–1138. 10.1161/circresaha.116.309421 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hannum, G. , Guinney, J. , Zhao, L. , Zhang, L. , Hughes, G. , Sadda, S. , … Zhang, K. (2013). Genome‐wide methylation profiles reveal quantitative views of human aging rates. Molecular Cell, 49(2), 359–367. 10.1016/j.molcel.2012.10.016 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hare, J. M. , Fishman, J. E. , Gerstenblith, G. , DiFede Velazquez, D. L. , Zambrano, J. P. , Suncion, V. Y. , … Heldman, A. W. (2012). Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy. JAMA, 308(22), 2369 10.1001/jama.2012.25321 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Harman, D. (1956). Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology, 11(3), 298–300. 10.1093/geronj/11.3.298 [PubMed] [CrossRef] [Google Scholar]

Harman, D. (1972). The biologic clock: The mitochondria? Journal of the American Geriatrics Society, 20(4), 145–147. 10.1111/j.1532-5415.1972.tb00787.x [PubMed] [CrossRef] [Google Scholar]

Harman, D. (2003). The free radical theory of aging. Antioxidants & Redox Signaling, 5(5), 557–561. 10.1089/152308603770310202 [PubMed] [CrossRef] [Google Scholar]

Hayashi, G. , & Cortopassi, G. (2015). Oxidative stress in inherited mitochondrial diseases. Free Radical Biology and Medicine, 88, 10–17. 10.1016/j.freeradbiomed.2015.05.039 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

He, Z. , Bian, J. , Carretta, H. J. , Lee, J. , Hogan, W. R. , Shenkman, E. , & Charness, N. (2018). Prevalence of multiple chronic conditions among older adults in Florida and the United States: Comparative analysis of the OneFlorida Data trust and national inpatient sample. Journal of Medical Internet Research, 20(4), e137 10.2196/jmir.8961 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Heidinger, B. J. , Blount, J. D. , Boner, W. , Griffiths, K. , Metcalfe, N. B. , & Monaghan, P. (2012). Telomere length in early life predicts life span. Obstetrical & Gynecological Survey, 67(5), 283–284. 10.1097/ogx.0b013e3182546dd0 [CrossRef] [Google Scholar]

Herbig, U. , Jobling, W. A. , Chen, B. P. C. , Chen, D. J. , & Sedivy, J. M. (2004). Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Molecular Cell, 14(4), 501–513. 10.1016/s1097-2765(04)00256-4 [PubMed] [CrossRef] [Google Scholar]

Herranz, N. , & Gil, J. (2018). Mechanisms and functions of cellular senescence. Journal of Clinical Investigation, 128(4), 1238–1246. 10.1172/jci95148 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hewitt, G. , Jurk, D. , Marques, F. D. M. , Correia‐Melo, C. , Hardy, T. , Gackowska, A. , … Passos, J. F. (2012). Telomeres are favoured targets of a persistent DNA damage response in ageing and stress‐induced senescence. Nature Communications, 3(1), 708 10.1038/ncomms1708 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hilmer, S. N. , & Le Couteur, D. G. (2016). Standardized, multidisciplinary approaches for the study of aging biology and for translation of aging interventions. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 71(4), 425–426. 10.1093/gerona/glv310 [PubMed] [CrossRef] [Google Scholar]

Hinken, A. C. , & Billin, A. N. (2018). Isolation of Skeletal Muscle Stem Cells for Phenotypic Screens for Modulators of Proliferation. Methods Mol Biol, 1787, 77–86. https://doi.org/0.1007/978-1-4939-7847-2_6 [PubMed] [Google Scholar]

Hoffman, J. M. , Lyu, Y. , Pletcher, S. D. , & Promislow, D. E. L. (2017). Proteomics and metabolomics in ageing research: From biomarkers to systems biology. Essays in Biochemistry, 61(3), 379–388. 10.1042/ebc20160083 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Holloway, G. P. , Holwerda, A. M. , Miotto, P. M. , Dirks, M. L. , Verdijk, L. B. , & van Loon, L. J. C. (2018). Age‐associated impairments in mitochondrial ADP sensitivity contribute to redox stress in senescent human skeletal muscle. Cell Reports, 22(11), 2837–2848. 10.1016/j.celrep.2018.02.069 [PubMed] [CrossRef] [Google Scholar]

Holton, N. W. , Ebenstein, Y. , & Gassman, N. R. (2018). Broad spectrum detection of DNA damage by Repair Assisted Damage Detection (RADD). DNA Repair, 66–67, 42–49. 10.1016/j.dnarep.2018.04.007 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10), R115 10.1186/gb-2013-14-10-r115 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Hughes, M. C. , Ramos, S. V. , Turnbull, P. C. , Nejatbakhsh, A. , Baechler, B. L. , Tahmasebi, H. , … Perry, C. G. R. (2015). Mitochondrial bioenergetics and fiber type assessments in microbiopsy vs. bergstrom percutaneous sampling of human skeletal muscle. Frontiers in Physiology, 6, 360 10.3389/fphys.2015.00360 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Jani, B. D. , Nicholl, B. I. , McQueenie, R. , Connelly, D. T. , Hanlon, P. , Gallacher, K. I. , … Mair, F. S. (2017). Multimorbidity and co‐morbidity in atrial fibrillation and effects on survival: Findings from UK Biobank cohort. EP Europace, 20(FI_3), f329–f336. 10.1093/europace/eux322 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Jim, H. S. L. , Sutton, S. K. , Small, B. J. , Jacobsen, P. B. , Wood, W. A. , Knight, J. M. , … Lee, S. J. (2016). Trajectories of quality of life after hematopoietic cell transplantation: Secondary analysis of blood and marrow transplant clinical trials network 0902 data. Biology of Blood and Marrow Transplantation, 22(11), 2077–2083. 10.1016/j.bbmt.2016.08.012 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Jiménez‐Chillarón, J. C. , Díaz, R. , Martínez, D. , Pentinat, T. , Ramón‐Krauel, M. , Ribó, S. , & Plösch, T. (2012). The role of nutrition on epigenetic modifications and their implications on health. Biochimie, 94(11), 2242–2263. 10.1016/j.biochi.2012.06.012 [PubMed] [CrossRef] [Google Scholar]

Jimenez‐Chillaron, J. C. , Hernandez‐Valencia, M. , Lightner, A. , Faucette, R. R. , Reamer, C. , Przybyla, R. , … Patti, M. E. (2006). Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight. Diabetologia, 49(8), 1974–1984. 10.1007/s00125-006-0311-7 [PubMed] [CrossRef] [Google Scholar]

Jodczyk, S. , Fergusson, D. M. , Horwood, L. J. , Pearson, J. F. , & Kennedy, M. A. (2014). No association between mean telomere length and life stress observed in a 30 year birth cohort. PLoS ONE, 9(5), e97102 10.1371/journal.pone.0097102 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Justice, J. N. , Gregory, H. , Tchkonia, T. , LeBrasseur, N. K. , Kirkland, J. L. , Kritchevsky, S. B. , & Nicklas, B. J. (2018). Cellular senescence biomarker p16INK4a+ cell burden in thigh adipose is associated with poor physical function in older women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 73(7), 939–945. 10.1093/gerona/glx134 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Jylhävä, J. , Pedersen, N. L. , & Hägg, S. (2017). Biological age predictors. Ebiomedicine, 21, 29–36. 10.1016/j.ebiom.2017.03.046 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Jylhävä, J. , Raitanen, J. , Marttila, S. , Hervonen, A. , Jylhä, M. , & Hurme, M. (2014). Identification of a prognostic signature for old‐age mortality by integrating genome‐wide transcriptomic data with the conventional predictors: The Vitality 90+ Study. BMC Medical Genomics, 7(1), 10.1186/1755-8794-7-54 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kadota, T. , Fujita, Y. , Yoshioka, Y. , Araya, J. , Kuwano, K. , & Ochiya, T. (2018). Emerging role of extracellular vesicles as a senescence‐associated secretory phenotype: Insights into the pathophysiology of lung diseases. Molecular Aspects of Medicine, 60, 92–103. 10.1016/j.mam.2017.11.005 [PubMed] [CrossRef] [Google Scholar]

Kananen, L. , Marttila, S. , Nevalainen, T. , Kummola, L. , Junttila, I. , Mononen, N. , … Jylhävä, J. (2016). The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: Evidence from two longitudinal studies. AGE, 38(3), 65 10.1007/s11357-016-9927-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kang, C. , Xu, Q. , Martin, T. D. , Li, M. Z. , Demaria, M. , Aron, L. , … Elledge, S. J. (2015). The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science, 349(6255), aaa5612–aaa5612. 10.1126/science.aaa5612 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kang, E. , Wang, X. , Tippner‐Hedges, R. , Ma, H. , Folmes, C. D. L. , Gutierrez, N. M. , … Mitalipov, S. (2016). Age‐related accumulation of somatic mitochondrial DNA mutations in adult‐derived human iPSCs. Cell Stem Cell, 18(5), 625–636. 10.1016/j.stem.2016.02.005 [PubMed] [CrossRef] [Google Scholar]

Kaushik, S. , & Cuervo, A. M. (2018). The coming of age of chaperone‐mediated autophagy. Nature Reviews Molecular Cell Biology, 19(6), 365–381. 10.1038/s41580-018-0001-6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kent, J. A. , & Fitzgerald, L. F. (2016). In vivo mitochondrial function in aging skeletal muscle: Capacity, flux, and patterns of use. Journal of Applied Physiology, 121(4), 996–1003. 10.1152/japplphysiol.00583.2016 [PubMed] [CrossRef] [Google Scholar]

Kim, S. , & Jazwinski, S. M. (2015). Quantitative measures of healthy aging and biological age. Healthy Aging Research, 4, 10.12715/har.2015.4.26 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kirkland, J. L. , & Tchkonia, T. (2017). Cellular senescence: A translational perspective. Ebiomedicine, 21, 21–28. 10.1016/j.ebiom.2017.04.013 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Kirkland, J. L. , Tchkonia, T. , Zhu, Y. , Niedernhofer, L. J. , & Robbins, P. D. (2017). The clinical potential of senolytic drugs. Journal of the American Geriatrics Society, 65(10), 2297–2301. 10.1111/jgs.14969 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Klionsky, D. J. (2014). Coming soon to a journal near you—the updated guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 10(10), 1691–1691. 10.4161/auto.36187 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Klionsky, D. J. , Cuervo, A. M. , & Seglen, P. O. (2007). Methods for monitoring autophagy from yeast to human. Autophagy, 3(3), 181–206. 10.4161/auto.3678 [PubMed] [CrossRef] [Google Scholar]

Knight, A. K. , Craig, J. M. , Theda, C. , Baekvad‐Hansen, M. , Bybjerg‐Grauholm, J. , Hansen, C. S. , … Smith, A. K. (2016). An epigenetic clock for gestational age at birth based on blood methylation data. Genome Biology, 17(1), 206 10.1186/s13059-016-1068-z [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Koppelstaetter, C. , Schratzberger, G. , Perco, P. , Hofer, J. , Mark, W. , Ollinger, R. , … Mayer, G. (2008). Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation. Aging Cell, 7(4), 491–497. 10.1111/j.1474-9726.2008.00398.x [PubMed] [CrossRef] [Google Scholar]

Laberge, R.‐M. , Zhou, L. , Sarantos, M. R. , Rodier, F. , Freund, A. , de Keizer, P. L. J. , … Campisi, J. (2012). Glucocorticoids suppress selected components of the senescence‐associated secretory phenotype. Aging Cell, 11(4), 569–578. 10.1111/j.1474-9726.2012.00818.x [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lanza, I. R. , & Nair, K. S. (2010). Mitochondrial metabolic function assessed in vivo and in vitro. Current Opinion in Clinical Nutrition and Metabolic Care, 13(5), 511–517. 10.1097/mco.0b013e32833cc93d [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lara, J. , Cooper, R. , Nissan, J. , Ginty, A. T. , Khaw, K.‐T. , Deary, I. J. , … Mathers, J. C. (2015). A proposed panel of biomarkers of healthy ageing. BMC Medicine, 13(1), 222 10.1186/s12916-015-0470-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Larsen, S. , Nielsen, J. , Hansen, C. N. , Nielsen, L. B. , Wibrand, F. , Stride, N. , … Hey‐Mogensen, M. (2012). Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. The Journal of Physiology, 590(14), 3349–3360. 10.1113/jphysiol.2012.230185 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Larsson, N.‐G. (2010). Somatic mitochondrial DNA mutations in mammalian aging. Annual Review of Biochemistry, 79(1), 683–706. 10.1146/annurev-biochem-060408-093701 [PubMed] [CrossRef] [Google Scholar]

Latimer, J. J. , & Kelly, C. M. (2014). Unscheduled DNA synthesis: the clinical and functional assay for global genomic DNA nucleotide excision repair. Methods Mol Biol, 1105, 511–532. 10.1007/978-1-62703-739-6_36 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lavker, R. M. , & Sun, T. T. (2000). Epidermal stem cells: Properties, markers, and location. Proceedings of the National Academy of Sciences, 97(25), 13473–13475. 10.1073/pnas.250380097 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lee, I. H. , Cao, L. , Mostoslavsky, R. , Lombard, D. B. , Liu, J. , Bruns, N. E. , … Finkel, T. (2008). A role for the NAD‐dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America, 105(9), 3374–3379. 10.1073/pnas.0712145105 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lev Maor, G. , Yearim, A. , & Ast, G. (2015). The alternative role of DNA methylation in splicing regulation. Trends in Genetics, 31(5), 274–280. 10.1016/j.tig.2015.03.002 [PubMed] [CrossRef] [Google Scholar]

Levine, M. E. , Lu, A. T. , Quach, A. , Chen, B. H. , Assimes, T. L. , Bandinelli, S. , … Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573–591. 10.18632/aging.101414 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Li, C. , Gao, W. , Gao, Y. , Yu, C. , Lv, J. , Lv, R. , … Li, L. (2018). Age prediction of children and adolescents aged 6–17 years: An epigenome‐wide analysis of DNA methylation. Aging, 10(5), 1015–1026. 10.18632/aging.101445 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Li, M. , Chen, M. , Han, W. , & Fu, X. (2010). How far are induced pluripotent stem cells from the clinic? Ageing Research Reviews, 9(3), 257–264. 10.1016/j.arr.2010.03.001 [PubMed] [CrossRef] [Google Scholar]

Li, Y. , Huang, J. , Pang, S. , Wang, H. , Zhang, A. , Hawley, R. G. , & Yan, B. (2017). Novel and functional ATG12 gene variants in sporadic Parkinson's disease. Neuroscience Letters, 643, 22–26. 10.1016/j.neulet.2017.02.028 [PubMed] [CrossRef] [Google Scholar]

Ligthart, S. , Marzi, C. , Aslibekyan, S. , Mendelson, M. M. , Conneely, K. N. , Tanaka, T. , … Dehghan, A. (2016). DNA methylation signatures of chronic low‐grade inflammation are associated with complex diseases. Genome Biology, 17(1), 255 10.1186/s13059-016-1119-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lin, J. , Cheon, J. , Brown, R. , Coccia, M. , Puterman, E. , Aschbacher, K. , … Blackburn, E. H. (2016). Systematic and cell type‐specific telomere length changes in subsets of lymphocytes. Journal of Immunology Research, 2016, 1–9. 10.1155/2016/5371050 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Lin, Y. , Damjanovic, A. , Metter, E. J. , Nguyen, H. , Truong, T. , Najarro, K. , … Weng, N.‐P. (2015). Age‐associated telomere attrition of lymphocytes in vivo is co‐ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions. Clinical Science, 128(6), 367–377. 10.1042/cs20140481 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Liu, L. , Cheung, T. H. , Charville, G. W. , & Rando, T. A. (2015). Isolation of skeletal muscle stem cells by fluorescence‐activated cell sorting. Nature Protocols, 10(10), 1612–1624. 10.1038/nprot.2015.110 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Liu, Y. , Sanoff, H. K. , Cho, H. , Burd, C. E. , Torrice,

How to Reinvent your Health - by Gary Mark Levin

The Kids Need a Diagnosis, Right? - by Edwin Leap

What happens when the parents search Google and/or ChatGPT

““Well, doctor, the thing is, my little Tricia here is eight and she has ADD, ADHD, PTSD, ODD and bipolar, with depression and anxiety. Of course, her daddy and I have schizoaffective with some ADHD and PTSD as well, and he’s bipolar but I’m not. But I have opioid use disorder, you see. Anyway, none of these here medicines are doing a thing for her. She keeps talking about dying and I really think she needs to be in the hospital for a few days to get things settled down.”

So much of this; so very much. And on the bed, a child with a coloring book and crayon, who may or may not look anxious or upset. Often, a child who is calm as can be when mom or dad aren’t in the room. Equally problematic, their parents have struggled with inner demons since their own childhoods; wounded adults, uncertain how to navigate their own problems, much less those of their children.

They grab what is offered to them. Lists of diagnoses offered by professionals. Diagnoses that frequently change over and over from year to year, crisis to crisis. Struggling parents, themselves bearers of many diagnostic labels and traumas who wouldn’t dare resist a new category if they thought it might help their children.

Now, I would never suggest that children can’t or don’t have mental illness. The last few years have brought us an explosion in pediatric and adolescent psychiatric issues. Indeed, an explosion that has far outstripped our resources and understanding. I know that most mental health professionals are doing their best in what must seem the psychic equivalent of the late pandemic. (And intricately connected to boot.)

What I don’t always get, what I struggle with, is the way our system is desperate to give these children assorted diagnoses, and to then sedate their developing brains with ever more potent drugs, the long term effects of which we really can’t begin to predict.

The field of mental health is complex. I have great respect for all of those who labor in it. However, for all of our advances psychiatric care has had a sometimes storied past. (Not throwing stones here; it’s true of all of medical science.)

Last Summer while on vacation with my wife’s family we toured the Transallegheny Lunatic Asylum, a tourist attraction in Weston, WV. From 1864 to 1994 this vast, stone building was actually a psychiatric hospital (with the term hospital being used in the loosest of manners for a good portion of its existence).

In fact, when I was in medical school at West Virginia University, a few years before the asylum closed, we actually toured this facility. I well remember the area where the criminally insane stayed; it was a sparse room where we walked past frightening and largely undressed men, milling about and sitting on bare benches.

These days it’s an interesting place that still has haunting echoes of a darker time when diagnoses of mental illness could be remarkably unscientific. (For a list, here’s a great link: https://mentalhealthathome.org/2020/02/24/lunatic-asylum-crazy-1864/)

There were times in the asylum when a man could put his wife and children away out of convenience. It was a place where PTSD might simply be diagnosed as “The War” and where even “Political Excitement” might land one in the facility. (Maybe that wasn’t such a bad one…)

Later in that dark place, where people now tour the halls on Halloween, frontal lobotomy was performed on many poor, helpless individuals. The very walls now seem embedded with suffering and loneliness, even on a Summer day.

Without a doubt, there were men, women, boys and girls who languished there with very real mental illness. And although the physicians, nurses and others did the best they knew in those times, they were wrong…a lot. Doubtless many of their therapies did far more harm than good. The unmarked graves on on the adjacent hillside are testament to the fact that all too many of those suffering in mind also perished in body in that lonely, Gothic building.

I suppose, when I see this desperate need that people have to apply diagnoses, or medications, which are not well understood, I think back to the asylum. In those days family members felt helpless in an era of limited science and had no idea how to help their troubled, frantic or catatonic loved ones; or they were nefarious and hoping to remove problematic individuals from their lives.

These days? I think the desire for even poor diagnostics and therapeutics, especially for children, has to do with several things. Of course, it’s related to the enormous amount of sympathy we try to extend to all of those with mental health issues.

In addition, it has to do with the reductionism of modern medicine in general and psychiatric care in particular. Unable to ascribe the woes of kids (or adults) to home, culture, economics, education, philosophy or theology, their problems have to be pathophysiologic. It’s why we give medications for ‘chemical imbalances’ without every really being able to see if we’ve rebalanced those naughty chemicals after all.

Finally, we have so many lonely, struggling parents and kids with a powerful need to belong to a group. Especially as the ancient bonds of family, clan and nation blow away like so much dust in the wind.

That new group may be defined by diagnoses, or equally often defined by being a caregiver for someone with a diagnosis. It’s very validating to know that one isn’t alone in the struggle. Unfortunately, I wonder sometimes if it doesn’t come much closer to Muchausen’s by Proxy as the need for an “in-group" may suggest the need for a diagnosis, rather than the opposite.

The asylum was great reminder that we have to be very, very careful when we become too comfortable in our understanding of the travails of the human psyche. It’s easy enough for us to look back on “hysteria” or “gathering in the head” and chuckle about the Neanderthals of our not so distant professional past. But I feel bad, not okay for those bygone patients but for their physicians who labored in much more of a scientific fog than we can imagine.

We might be wiser to wonder who will shake their heads and tsk tsk in the future when they see how many adults and children alike in our time walked around, on brain bending chemicals, for the often poorly understood diagnoses we so casually apply.

I fear we’re not so far from that old asylum as we might think. And that makes me sad for the brokenness and helplessness we all feel these days.

The Kids Need a Diagnosis, Right? - by Edwin Leap

Common symptoms of long Covid identified in new scientific research

The new research is meant to help scientists move forward in finding a treatment for a condition that still plagues millions of Americans.

A long-awaited study that zeroes in on the most common groups of symptoms for people with long Covid may not bring the relief millions of Americans and doctors have been wanting.

The study, some of the first research from the National Institutes of Health’s billion-dollar RECOVER program, does not provide a standardized definition of the condition. Researchers say it is a first step in identifying a "common language" for scientists working toward treatments for the condition.

"I think that the amount of science that's going to come after this is going to be an avalanche," said study author Dr. Leora Horwitz, a professor of population health and medicine at New York University Grossman School of Medicine, as well as the director of the Center for Healthcare Innovation and Delivery Science at NYU Langone Health.

The new study, published Thursday in the Journal of the American Medical Association, looked at data from 9,764 adults in the RECOVER trial, which has been recruiting participants since last year. The vast majority, 8,646 people, had previously been diagnosed with Covid. 

Long Covid defies definition.  There are many protean symptoms that overlap with other disease states. Chronic fatigue syndrome which is now called Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) .

While hundreds of symptoms possibly associated with long Covid have long been reported — mostly through anecdotes from patients — the new study homes in on 12 of the most common.

Ongoing fatigue.

Brain fog.

Dizziness.

Thirst.

Cough.

Chest pain.

Heart palpitations.

Abnormal movements.

Upset stomach.

Lack of sexual desire.

Loss of smell or taste.

Feeling sick or overly exhausted after physical activity, also known as post-exertional malaise.

There are some biomarkers associated with Long Covid, also known as Long Haul Covid. This list is exhaustive and non-specific and may occur in other inflammatory and autoimmune conditions.

A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves

The answers thus far are nonspecific and no specific treatments are available other than the usual attempt to maintain good nutrition, exercise and a wellness approach to minimizing symptoms.

Common symptoms of long Covid identified in new scientific research

SHORTCUTS TO HELL. In the “Wild West” of Outpatient Vascular Care, Doctors Can Reap Huge Payments as Patients Risk Life and Limb

 

In the “Wild West” of Outpatient Vascular Care, Doctors Can Reap Huge Payments as Patients Risk Life and Limb

by Annie Waldman

ProPublica is a Pulitzer Prize-winning investigative newsroom. Sign up for The Big Story newsletter to receive stories like this one in your inbox.

Series: Arterial Motives

The Big Business of Clogged Arteries

In the suburbs of Maryland, Dr. Jeffery Dormu’s presence is hard to miss. He’s a regular on the local TV station, which has featured him and his practice five times over the past five years. And he smiles down from an electronic billboard outside a three-story vascular center he calls The Watcher. “It has a biblical reference, which is to watch over the community,” he said at its 2018 opening. In response to the country’s “tragedy of cardiovascular disease,” the center trademarked the phrase “vascular devastation,” a slogan frequently invoked in its marketing, along with a claim to have “saved over 34,000 lives and limbs.”

Dormu and his group, the Minimally Invasive Vascular Center, have been a magnet for people with leg pain who worry they have peripheral artery disease, a condition that afflicts more than 6.5 million Americans and happens when fatty deposits narrow the arteries and block blood from flowing to the legs.

But Dormu’s portrayal of his practice as a heroic refuge hid a distressing statistic: The vascular surgeon was performing an invasive leg treatment more often than almost any other doctor in the country, even when his patients didn’t need it and even as evidence of harm mounted.

One man had to have his leg amputated after Dormu administered multiple invasive treatments for mild pain, according to legal filings. A 62-year-old grandmother bled out and died shortly after Dormu cut into her, according to another lawsuit.

Dormu’s go-to procedure, the atherectomy, involved shaving blockages with blade-topped catheters. Best practices recommend that doctors hold off on invasive procedures like these, which can lead to complications including limb loss, on patients in the earliest stages of disease; doctors should first see how the patients do with exercise and medication. Dormu defaulted to atherectomies almost immediately, patient legal and medical records show.

Four years ago, leading researchers warned the Centers for Medicare and Medicaid Services that some doctors were potentially abusing interventions. The researchers implored the government insurer to scrutinize its own data to identify overuse, noting that some of the doctors could present an “immediate threat to public safety.”

There is no public evidence that CMS meaningfully responded.

But a ProPublica analysis of CMS data suggests that if the agency had reviewed its own figures, it would have discovered that Dormu was part of a small pool of physicians performing a disproportionate number of treatments. From 2017 to 2021, the analysis shows, the top 5% of doctors conducting atherectomies — about 90 physicians overall — accounted for more than a third of all procedures and government payments, totaling nearly a billion dollars.

Near the top of the list sits Dormu, logging more atherectomies — and making more money from them — than almost every other doctor in America.

CMS paid Dormu more than $30 million in the past decade for vascular procedures he performed on hundreds of patients.

Dormu declined to be interviewed and did not respond to emailed questions.

But a chorus of experts told ProPublica that the federal government’s decision to provide unconditional payments for vascular procedures — and then not pay attention to what happened — is a prime example of what’s wrong with the American health care system.

“The government is really to blame for setting these tremendously high reimbursement values without looking into whether these procedures are helping people or are just worthless procedures or, in fact, are hurting people,” said Dr. Dipankar Mukherjee, a vascular surgeon and chief of vascular surgery at Inova Fairfax Hospital in Virginia.

CMS kicked off the problem 15 years ago when it tried to rein in the swelling hospital costs for vascular care. Over the past few decades, advances in technology allowed patients with serious circulation problems to avoid open surgery and instead undergo minimally invasive treatment with cutting-edge devices. As they flocked to hospitals for these procedures, patients with clogged leg arteries became even more expensive than patients with clogged heart arteries.

In 2008, recognizing that the procedures could be done safely and more efficiently outside hospitals, CMS officials turbocharged payments to doctors’ offices that deployed balloons and stents to widen arteries. And in 2011, they began to reimburse those offices for atherectomies.

Before the change, an office provider inserting a stent could make about $1,700 from Medicare; deploying a balloon could bring in roughly $3,800. By 2011, the payments rose to about $6,400 and $4,800 respectively. But nothing compared to the payout for atherectomies conducted in offices: about $13,500 per procedure, as opposed to roughly $11,450 in a hospital.

Instead of saving money, the government started a boom.

Atherectomies increased by 60% from 2011 to 2014; Medicare’s overall costs for peripheral vascular treatments climbed by nearly half a billion dollars, or 18%.

The government insurer didn’t change course in 2014, when research began to indicate that atherectomies may not be more effective than cheaper alternatives, or in 2019, when experts warned the procedure may be associated with a higher risk of complications.

From 2013 to 2021, the most recent year of Medicare data, the number of atherectomies has doubled and payments to doctors have nearly tripled, totaling about $503 million in 2021.

“There are definitely places where atherectomy is very helpful,” said Dr. Caitlin Hicks, an associate professor of surgery at Johns Hopkins University School of Medicine. “But it’s definitely being used inappropriately, and that’s when bad things happen.”

Experts fear patients are being caught up in a new era of profit-driven procedure mills, in which doctors can deploy any number of devices in the time it takes to drill a tooth and then bill for the price of a new car.

The generous reimbursements have created a conflict of interest for doctors running their own practices, who are supposed to make unbiased medical decisions while also being responsible for a lease, overhead and staff. And unlike hospitals, which have panels and administrators who spot adverse events and questionable billing, these offices don’t face such scrutiny.

CMS, experts say, should step up: It could reduce its reimbursements or even investigate doctors with outsized procedure patterns.

ProPublica reached out to CMS more than two weeks ago, listing the facts in this story, asking questions and requesting an interview. CMS did not make an official available to talk or provide any written answers.

“Vascular medicine now is the frontier of the Wild West,” said Dr. Marty Makary, a professor of surgery and health care quality researcher at Johns Hopkins University School of Medicine. “People are flying blind walking into the clinics of these doctors with egregious practice patterns, and we know that their pattern is indefensible.”

It was at the cusp of this lucrative new era in vascular medicine that Dormu, an ambitious young doctor from Washington, D.C., entered the scene.

After earning his medical degree at the New York Institute of Technology College of Osteopathic Medicine and completing an additional eight years of training in New York and New Jersey hospitals, including a residency in general surgery and two fellowships in cardiothoracic and vascular surgery, he received his license to practice medicine in Maryland in 2007. That year, he founded the Minimally Invasive Vascular Center.

“People in general are just afraid of surgery,” he later told a local TV journalist. “They can get by with minimally invasive surgery, a needle puncture without having to be cut, without having to worry about an amputation. They walk in and within hours they walk out, and pretty much healed.”

Dormu opened several vascular offices in the region. At one point, his group also partnered with the Washington, D.C., Department of Aging and Community Living, providing hundreds of free vascular screenings for elderly patients at senior centers and residences across the capital.

But according to public records and lawsuits, as his profile and his practice grew, so, too, did evidence of harm.

In March 2016, while he was performing an elective aorta repair at Providence Hospital, the patient began to hemorrhage, according to a District of Columbia Board of Medicine document on the incident. After trying to control the bleeding, Dormu transferred the patient to the intensive care unit for resuscitative efforts and then left the hospital for his private practice and other appointments.

He was gone for more than two hours, and in that time, hospital staff couldn’t reach him. The hospital patient died in the recovery room from hemorrhage and organ failure, the report said. Six years later, the District of Columbia Board of Medicine would reprimand him for the incident alongside a $5,000 fine, finding that he abandoned a patient in need of further emergency care, “knowing the high risk of mortality and without adequate communication to other hospital staff.”

The death of the patient did not interfere with his medical license or appear to slow his career.

Nine months later, a mechanic sought his care for mild leg pain. As the owner of his shop, Steve Rosenberg clocked long hours, six days a week, repairing anything with wheels or an engine. But as he reached his mid-50s, the long days of standing under vehicle lifts had begun to strain his legs.

His primary care doctor suggested that he see a vascular specialist and handed him a list of physicians to choose from. Dormu happened to have an office in the same plaza as Rosenberg’s auto shop, between a jujitsu studio and a dentist’s office.

He first visited Dormu’s practice that December.

Instead of starting with more conservative treatment, Dormu deployed a trifecta of interventions on both of Rosenberg’s legs within three months, widening his arteries with stents and balloons, and debulking his vessels with atherectomy devices, according to later legal filings.

Shortly after one of the procedures, Rosenberg’s left foot grew numb and was cool to the touch. He went to the emergency room, where doctors discovered that one of his stents had clogged, hindering his vessel from carrying blood.

Dormu called him back to his office, where he repeated the procedures: shaving the blockages, ballooning the artery walls, and installing another stent.

The next day, he repeated the procedures again, ballooning his vessels and installing yet another stent.

Dormu sent Rosenberg to Providence Hospital in Washington, D.C., for further treatment. Within a day, his left foot had grown cold, a sign that blood likely no longer flowed freely through his vessels.

According to the terms of a legal settlement in a malpractice suit against Dormu, Rosenberg cannot comment on his care. However, public documents filed in his case, including assessments from medical experts, illuminate the cascade of procedures and the outcome.

A vascular surgeon Dormu retained for his defense, Dr. Garry Ruben, said the interventions were warranted; he said Rosenberg had been prescribed an anti-platelet medication, which he did not consistently take. In legal filings, Dormu blamed Rosenberg’s injuries on his preexisting medical conditions and circumstances outside his control.

However, after reviewing medical records and diagnostic studies, Dr. Christopher Abularrage, an expert retained by Rosenberg and a professor at Johns Hopkins who specializes in vascular and endovascular surgery, found several “breaches of the standard of care.” He found that Dormu had failed to prescribe conservative therapy and lifestyle modifications first and “persisted with unindicated, endovascular interventions in the face of persistently poor outcomes and diminishing returns.”

In less than six months, Rosenberg had been transformed from a patient with mild leg pain to one with a high risk of limb loss, he concluded.

Rosenberg spent nearly a week at Providence Hospital, the life slowly draining from his leg, before he was transferred to Washington Hospital Center on April 8, 2017, according to records. By then, his left leg was gangrenous and had no pulse. All of the stents had become blocked.

Without better options, doctors amputated his leg.

Between 2013 and 2017, Dormu earned about $14.5 million from Medicare — more than 99% of other vascular surgeons across the country — for treating hundreds of patients a year, the vast majority of them in his clinics.

In 2018, he was able to afford an upgrade.

The Watcher was not like other surgical centers. At its entrance stood a juice bar that could serve organic cold-pressed drinks to patients. Crystal chandeliers adorned its hallways. Moist air was pumped through its vents. And more than a dozen original modern paintings lined its walls, making it feel like an art gallery. “We wanted it to give that shock and awe,” Dormu said in a video interview from the facility’s opening day.

His clinic provided a litany of medical services, including treatments for uterine fibroids, erectile dysfunction and varicose veins, and elective nonsurgical fat reduction.

The expansive facility boosted Dormu’s earnings. From 2018 through 2021, he earned nearly $18 million in Medicare payments for all of his clinic’s activities.

One procedure stood out from the rest: Nearly $12 million of that came from atherectomies, according to Medicare data.

He performed one on Alice Belton, a high school nursing teacher who sought help in 2018 for lower extremity pain, numbness, and tingling. Her artery blood flow was normal; even Dormu noted that she didn’t have severe leg pain, according to an ongoing lawsuit. And yet, he conducted multiple procedures over about a year, shaving plaque, ballooning her vessels, treating her veins and running invasive scans; the procedures were unnecessary, according to a medical expert retained in her case.

Belton says she has since developed permanent nerve damage in her leg, which has prevented her from working full-time. In legal filings, Dormu denied the allegations and claimed that the alleged injuries were caused by preexisting conditions.

“The experience with Dr. Dormu has shaken my confidence in health care practitioners and more importantly in myself,” she said. “I feel duped that this surgeon convinced me, a nurse, that my problems required such radical surgical interventions.”

And then there was John Malinich, who had no leg pain but wanted to get his circulation checked in 2019 after he saw Dormu’s billboard. At first, Malinich didn’t question Dormu’s treatments; the doctor’s confident demeanor and lavish facility impressed him and put him at ease.

“After surgery on both of my legs, they wanted me to go back and do it over again,” he said. “After that, I started getting suspicious.”

He said he got a second opinion from another vascular surgeon who informed him that the prior procedures, which involved balloons, an atherectomy and a stent, had been unnecessary. To ensure his stent doesn’t collapse or clog, doctors now have to annually monitor Malinich. He filed a lawsuit against Dormu, who has denied allegations of overtreatment. The case is ongoing.

“I trusted the guy,” Malinich said. “But it was just to make money.”

The next year, Heather Terry was looking forward to her mother’s return home after a six-month stint rehabilitating in a nursing home. For years, Heather had helped take care of 62-year-old Linda Terry, who had debilitating epilepsy. After a fall down a flight of stairs and subsequent back surgery, Terry was left paraplegic and unable to walk.

Just before she was supposed to be discharged from the nursing home in August 2020, the staff told Heather Terry that her mother had leg pain and ulcers on her heels that needed treatment. According to her family, Linda Terry had no prior circulation issues. The procedure was simple, the staff said, and would be conducted in a clinic just down the road.

On Aug. 13, Terry was transferred to Dormu’s center, where he started an atherectomy procedure, inserting the small tube capped with blades into her vessels to shave the plaque from her artery walls.

Less than 15 minutes into the treatment, her blood pressure began to drop.

With atherectomy, there’s always a risk that the device may dissect the vessel, which would require immediate care.

Dormu aborted the procedure and brought Terry into the recovery area. She was drowsy and her blood pressure continued to waver, signs that she may have been bleeding internally, according to her family’s attorney. Instead of being rushed to the emergency room, legal filings show, she was sent back to the nursing home, where she became unresponsive.

The nursing home called an ambulance, which ferried her to the emergency room at the University of Maryland Laurel Medical Center. Three hours later, she was pronounced dead, according to the lawsuit, a consequence of severe anemia due to internal blood loss.

For the aborted procedure, according to the family’s attorney, Dr. Zev Gershon, Dormu charged her insurance about $20,000.

Heather Terry believes that if Dormu had treated her mother with appropriate care and transferred her directly to the hospital, she might have survived. “It went from ‘She’s going to come home tomorrow’ to ‘She’s dead,’” said Terry, whose ongoing malpractice case against Dormu is set to go to trial this year.

In legal filings, Dormu denied any involvement in her mother’s death. He said in a deposition that he did not see evidence of bleeding and that Linda Terry’s anemia could have been due to a prior fall. He said he also gave a directive to send her to the hospital after the aborted procedure, despite EMS records obtained by the family’s attorney showing that Terry was sent back to the nursing home.

“I trusted doctors,” Heather Terry said, “but now I’m starting to think that maybe they shouldn’t be as fully trusted.”

By 2021, Dr. Kim Hodgson, a former president of the Society for Vascular Surgery, recognized that unfettered profiteering in his field was not just a threat to patients, it also stood to damage the credibility of his specialty. Notably, abuse in outpatient vascular facilities was the No. 1 complaint he had received from members. That August, the vascular surgeon stood before hundreds of doctors at the society’s annual conference and made a plea.

“Somebody has to address what should never have been allowed to get to this level of threat to us and our patients in the first place,” he said. “We can play whack-a-mole every time the bad actors surface until the cows come home, but that leaves a trail of harmed patients and wasted resources.”

In dozens of slides, he laid out evidence exposing the magnitude of the crisis: the Medicare incentive, the explosive growth of procedures in clinics and the potential for inappropriate treatment. Most critically, he warned about the risk of patient harm. In recent years, researchers have found that patients in the early stages of vascular disease had less than a 2% risk of amputation after five years. However, with aggressive interventions, that risk could surge up to 5% or even 10%.

“The problem is that these behaviors — unindicated early interventions and overuse of unproven technologies — still have costs and more often than not, those costs are borne by our patients,” he said. “We can and should do better, otherwise we are also enablers.”

The issue has magnified into a crisis that has splintered the specialties that conduct these procedures, which include interventional radiologists, cardiologists as well as vascular surgeons. Some physicians do not view overuse as an urgent problem and feel the recent academic attention unfairly stigmatizes private practice doctors.

“The majority of operators are doing the right thing,” said Dr. Jeffrey Carr, an interventional cardiologist and the founding president of the Outpatient Endovascular and Interventional Society, which represents physicians working in outpatient settings. “We need to call out the bad actors, but to cast a narrative that puts us all in the same arena is wrong.”

Other doctors recognize a need for considerable reforms.

CMS could reverse the change that kicked off the entire problem, some experts said, by reducing its outpatient reimbursement rates. “If you shut off the money, the whole thing will stop tomorrow,” Mukherjee, the Virginia vascular surgeon, said.

But such cuts might hurt doctors practicing responsibly and could even nudge the least scrupulous ones into higher gear to make up the financial difference. “You could incentivize people to do more procedures, and some of them may be inappropriate,” said Dr. Peter Lawrence, the former chief of vascular and endovascular surgery at the University of California, Los Angeles, who developed an outpatient center connected to the university.

More critical than payment cuts, Lawrence said, is greater oversight of office-based facilities. Many states don’t require doctors in those settings to have special vascular training or hospital privileges in case of complications, he said. “You could be a psychiatrist and do these procedures,” he said.

Many physicians also support improved data collection, particularly for newer technologies like atherectomy, to ensure that they’re not only safe but result in improved outcomes.

“Many of the vascular procedures that are done are relatively safe or can be done with good short-term results, but the failures are long term — it’s what happens in two to five years,” Lawrence said. “Unless you have a reimbursement system, which not only pays you for the initial procedure but whether or not it’s durable, you can have procedures done in our society that have great short-term results but have poor long-term results.”

CMS could require physicians to participate in patient registries, said Dr. William Schuyler Jones, an interventional cardiologist and associate professor of medicine at Duke University School of Medicine. “That type of required reporting would make our system better,” he said, “and would ultimately put the onus on all of us to do more appropriate care.”

For Dormu, patients were the ones to prompt accountability, airing their grievances to the Maryland Board of Physicians. Among them was a woman who sought his care for excessive leg itching and said he tried to pressure her into an invasive artery scan. When she sought a second opinion, the doctor concluded that her itching likely stemmed from a reaction to an insect bite.

The medical board examined the records of 11 of Dormu’s patients. Two peer reviewers, board certified in vascular surgery, independently concluded that Dormu had performed “medically unnecessary and invasive vascular procedures” and failed to meet appropriate standards of care for 10 of the 11 patients, “exposing them to potential risks such as bleeding, infection, blood vessel injuries which could acutely or chronically worsen the patient’s circulation, and limb loss.”

One patient who sought Dormu’s care to evaluate blockages in their legs could walk a mile before treatment, but after the procedures, they could not walk at all.

“There exists a substantial likelihood of risk of serious harm to the public health, safety, and welfare in Dr. Dormu’s continued practice,” the board’s executive director, Christine Farrelly, concluded.

Last October, the board found him in violation of state medical law, citing his overuse of procedures and his failure to uphold standards of care. It fined him $10,000, suspended him and put him under a two-year probation, during which he must be supervised and enroll in an ethics course.

Maryland Department of Health spokesperson Chase Cook said the agency’s Office of Health Care Quality, which is responsible for oversight of the state’s surgical centers and licensed Dormu’s current facility, was not aware of his sanctions nor the allegations of harm. The office “will follow-up in accordance with federal and state regulations,” Cook said.

Despite lacking an active license to practice medicine in Maryland, Dormu is still listed on his clinic’s website as the lead vascular surgeon, “currently available for office visits and in-patient consultations.”

When ProPublica called Dormu’s office to inquire whether he was still practicing, the receptionist said he was no longer seeing patients and that “Dr. Seibles” was providing all the same services. According to the Virginia Board of Medicine’s directory, Dr. Ayana Jonelle Seibles spends 20% of her time practicing at Dormu’s center in Maryland.

An emergency medicine physician who does not have specialty training in vascular surgery, Seibles appears to have a close relationship with Dormu; according to county property tax records, they have owned a home together since at least 2017. Seibles did not respond to ProPublica’s questions that were sent by email.

In a lawsuit deposition last month, Dormu said that he stopped doing surgery this year as a “personal choice.” When asked the name of his supervisor, he stated that he couldn’t recall it. He also couldn’t recall how many times he had been sued for malpractice, any of the details of the cases, nor the names of the attorneys representing him. He also couldn’t specify how many atherectomies he had performed, only estimating that he had done more than 100.

According to Medicare data, over the past decade, he has done at least 3,400.

For most of his life, Rosenberg trusted doctors; his own father was one. But the mechanic has lost faith in medicine. Memories of his 2017 amputation have been largely buried by the trauma, but he recalls lying in his hospital bed after the operation, the remnants of his left leg wrapped in a cloud of white bandages. “Life isn’t supposed to turn out like this,” he said.

He was discharged to his three-story colonial home, where two steps led to the front door and 13 steps gave way to the second floor; he could only ascend them by crawling backward. Eventually, he sold the house and his family moved into a flat, ranch-style home.

He tried to maintain his auto shop, relying on his wife and teenage stepson to help out. But with his limited mobility, first in a wheelchair and later maneuvering with his prosthetic and a cane, he could not repair cars like he used to and was forced to sell his business and retire.

Before, he could get dressed and out the door in less than 30 minutes; it now takes more than an hour. He used to prepare meals for his family, but after, his stepson had to learn how to cook. In the months following the surgery, he often fell asleep by 7:30 p.m., tired from carrying his body around all day. Discomfort would awaken him by 4 a.m.

Half of his days are now spent navigating the complex web of amputee providers, arguing with insurance agents, attending physical therapy and meeting with specialists to keep his vascular system in check.

Above all, managing the pain has remained a lingering burden. Even though he lost most of his left leg, its memory has been indelibly burned into his brain, haunting him like a phantom. Sometimes the bottom of his missing foot itches or a jolt surges down his absent calf.

“And there’s nothing anyone can do about it,” he said, “because it’s not there.”

In the end game, science and medicine are limited by 'clinical judgment'.  A very subjective term difficult to measure.  Primum non nocere .