Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2019, Vol. 10 Issue (4) : 883-900     DOI: 10.14336/AD.2018.1030
Review |
Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways
Georg Fuellen1,*, Ludger Jansen2,*, Alan A Cohen3, Walter Luyten4, Manfred Gogol5, Andreas Simm6, Nadine Saul7, Francesca Cirulli8, Alessandra Berry8, Peter Antal9,10, Rüdiger Köhling11, Brecht Wouters12, Steffen Möller1
1Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Aging Research (IBIMA), Rostock, Germany.
2Institute of Philosophy, University of Rostock, Germany.
3Department of Family Medicine, University of Sherbrooke, Sherbrooke, Canada.
4KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
5Institute of Gerontology, University Heidelberg, Germany.
6Department of Cardiac Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
7Humboldt-University of Berlin, Institute of Biology, Berlin, Germany.
8Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Italy.
9Budapest University of Technology and Economics, Budapest, Hungary.
10Abiomics Europe Ltd., Hungary.
11Rostock University Medical Center, Institute for Physiology, Rostock, Germany.
12KU Leuven, Department of Biology, Leuven, Belgium
Download: PDF(522 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one’s health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of physiological, cognitive, physical and reproductive function, and a lack of disease. We further define aging as the aggregate of all processes in an individual that reduce its wellbeing, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts.

Keywords terminology      health      aging      biological age      wellbeing      biomarker     
Corresponding Authors: Fuellen Georg,Jansen Ludger   
About author:

These authors contributed equally to this work.

Just Accepted Date: 19 November 2018   Issue Date: 01 August 2019
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Georg Fuellen
Ludger Jansen
Alan A Cohen
Walter Luyten
Manfred Gogol
Andreas Simm
Nadine Saul
Francesca Cirulli
Alessandra Berry
Peter Antal
Rüdiger Köhling
Brecht Wouters
Steffen Möller
Cite this article:   
Georg Fuellen,Ludger Jansen,Alan A Cohen, et al. Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways[J]. Aging and disease, 2019, 10(4): 883-900.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2018.1030     OR     http://www.aginganddisease.org/EN/Y2019/V10/I4/883
StateTime periodUnderlying biological processesPredictor of future state
Single conceptshealthhealthspanhealthspan-enhancing processeshealth biomarkers
survivallifespanlifespan-enhancing processessurvival biomarkers
Integrative concepts…wellbeing“wellspan”wellspan-enhancing processesbiological age
… and their oppositesillbeing“illspan”aging processes
Baseline referencebaseline organismal statechronological timeaverage biological processeschronological age
Table 1  Framework of definitions.
Featurelimited to speciespathologicalReferences
physiological function
stress resistance[17-21], cf.
 thermo-tolerance (=heat shock tolerance)[22, 23]
 hypoxic stress tolerance[24, 25]
 osmotic stress tolerance[26]
 oxidative stress tolerance[19, 23, 27]
 metabolic status / homeostasisxcf.[2], cf. [28 29]
 redox status / homeostasisx[30, 31]
 immune status / homeostasisxcf. [20, 32]

physical & cognitive function (=strength and cognition)
 motivated/stimulated locomotion(worm)[33]
 (motor) balance, dexterityhuman/mouse[34-38]
 muscle/neuronal/intestinal integrityx[39-41]

 physical function (=strength)
  [unmotivated/unstimulated] locomotioncf. [18, 20, 42, 43]
  grip strengthhuman/mousecf. [20, 44, 45]
  pharyngeal pumpingworm[18, 22, 46, 47]
  gait speed, chair risinghuman/ (mouse)cf. [20, 48, 49]
  muscle integrityx[40, 41]

 cognitive function (=cognition)
  sensory perceptioncf. [20, 50-52]
  (short-term) memory,
processing speed
(human/ mouse)[53-56]
  sleep, cardiac rhythmcf. [20, 57]
  executive/verbal functionhuman/ mouse[58, 59]
  neuronal integrityx[60]

reproductive function
 number of offspring[61-64]
 offspring health/survival[65, 66]

lack of frailty, Healthy Aging Index (and similar), allostatic load; lack of physiological dysregulation, self-reported health, quality of life(human)[2, 67-74]

(prodromal) organ/physiological function (heart/cardiovascular, neurological, etc.)
(prodromal) paralysis, protein aggregation/plaques
human/animal modelxcf. [20, 75, 76]

lack of disease and medications(human)e.g., [77, 78]
Table 2  Features contributing to a definition of health.
[1] Kaeberlein M, Rabinovitch P, Martin G (2015). Healthy aging: The ultimate preventative medicine. Science, 350: 1191-1193.
[2] Niedernhofer L, Kirkland J, Ladiges W (2017). Molecular pathology endpoints useful for aging studies. Ageing research reviews, 35: 241-249.
[3] Luyten W, Antal P, Braeckman B, Bundy J, Cirulli F, Fang-Yen C, et al. (2016). Ageing with elegans: a research proposal to map healthspan pathways. Biogerontology, 17: 771-782.
[4] Fuellen G, Schofield P, Flatt T, Schulz RJ, Boege F, Kraft K, et al. (2016). Living Long and Well: Prospects for a Personalized Approach to the Medicine of Ageing. Gerontology, 62: 409-416.
[5] Bedau M2008. What is life? In A Companion to the Philosophy of Biology. Sarkar S, and Plutynski A, editors: Malden MA: Blackwell. 455-471.
[6] Murphy D 2015. Concepts of Disease and Health. In The Stanford Encyclopedia of Philosophy. Zalta E, editor. https://plato.stanford.edu/archives/spr2015/entries/health-disease/.
[7] Sadegh-Zadeh K 2012. Handbook of Analytic Philosophy in Medicine: Springer.
[8] WHO. 2018. Constitution of WHO: principles. www.who.int/about/mission/en/.
[9] WHO. 2018. Classification of Diseases (ICD). www.who.int/classifications/icd/en.
[10] WHO. 2018. International Classification of Functioning, Disability and Health (ICF). www.who.int/classifications/icf/en/.
[11] Murray CJ, Barber RM, Foreman KJ, Abbasoglu Ozgoren A, Abd-Allah F, Abera SF, et al. (2015). Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet, 386: 2145-2191.
[12] Hertel J, Frenzel S, König J, Wittfeld K, Fuellen G, Holtfreter B, et al. (2018). The informative error: A framework for the construction of individualized phenotypes. Stat Methods Med Res, [Epub ahead of print].
[13] Baker GT 3rd, Sprott RL (1988). Biomarkers of aging. Experimental gerontology, 23: 223-239.
[14] Barton A, Burgun A, Duvauferrier R 2012. Probability assignments to dispositions in ontologies. In Proceedings of the 7th International Conference on Formal Ontology in Information Systems (FOIS). Donnelly M, and Guizzardi G, editors: Amsterdam: IOS Press. 3-14.
[15] Barton A, Jansen L, Ethier J2018. A taxonomy of disposition-parthood. FOUST II: 2nd Workshop on Foundational Ontology. In Proceedings of the Joint Ontology Workshops 2017. Galton A, and Neuhaus F, editors. 1-10.
[16] Pöthig D, Simm A (2011). Brücken zwischen Experten schlagen: Vitalität, Gesundheitsressourcen und Biofunktionales Alter(n). Bewegungstherapie und Gesundheitssport, 27: 57-63.
[17] Rodriguez M, Snoek L, de Bono M, Kammenga J (2013). Worms under stress: C. elegans stress response and its relevance to complex human disease and aging. Trends Genet, 29: 367-374.
[18] Leonov A, Arlia-Ciommo A, Piano A, Svistkova V, Lutchman V, Medkour Y, et al. (2015). Longevity extension by phytochemicals. Molecules, 20: 6544-6572.
[19] Dues D, Andrews E, Schaar C, Bergsma A, Senchuk M, Van Raamsdonk J (2016). Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways. Aging (Albany NY), 8: 777-795.
[20] Fischer KE, Hoffman JM, Sloane LB, Gelfond JA, Soto VY, Richardson AG, et al. (2016). A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging, 8: 2370-2391.
[21] Keith S, Amrit F, Ratnappan R, Ghazi A (2014). The C. elegans healthspan and stress-resistance assay toolkit. Methods, 68: 476-486.
[22] Eckers A, Jakob S, Heiss C, Haarmann-Stemmann T, Goy C, Brinkmann V, et al. (2016). The aryl hydrocarbon receptor promotes aging phenotypes across species. Sci Rep, 6: 19618.
[23] Bansal M, Zhu L, Yen K, Tissenbaum H (2015). Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proceedings of the National Academy of Sciences of the United States of America, 112: E277-E286.
[24] Mabon M, Scott B, Crowder C (2009). Divergent mechanisms controlling hypoxic sensitivity and lifespan by the DAF-2/insulin/IGF-receptor pathway. PLoS One, 4: e7937.
[25] Powell-Coffman J (2010). Hypoxia signaling and resistance in C. elegans. Trends Endocrinol Metab, 21: 435-440.
[26] Lamitina S, Strange K (2005). Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress. Am J Physiol Cell Physiol, 288: C467-C474.
[27] Ding A, Zheng S, Huang X, Xing T, Wu G, Sun H, et al. (2017). Current Perspective in the Discovery of Anti-aging Agents from Natural Products. Nat Prod Bioprospect, 7: 335-404.
[28] Bettedi L, Foukas LC (2017). Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing. Biogerontology.
[29] Braeckman B, Houthoofd K, De Vreese A, Vanfleteren J (2002). Assaying metabolic activity in ageing Caenorhabditis elegans. Mech Ageing Dev, 123: 105-119.
[30] Go Y, Jones D (2013). Thiol/disulfide redox states in signaling and sensing. Crit Rev Biochem Mol Biol, 48: 173-181.
[31] Back P, De Vos W, Depuydt G, Matthijssens F, Vanfleteren J, Braeckman B (2012). Exploring real-time in vivo redox biology of developing and aging Caenorhabditis elegans. Free Radic Biol Med, 52: 850-859.
[32] Youngman M, Rogers Z, Kim D (2011). A decline in p38 MAPK signaling underlies immunosenescence in Caenorhabditis elegans. PLoS genetics, 7: e1002082.
[33] Churgin M, Jung S, Yu C, Chen X, Raizen D, Fang-Yen C (2017). Longitudinal imaging of Caenorhabditis elegans in a microfabricated device reveals variation in behavioral decline during aging. eLife, 6: e26652.
[34] Abrahamová D, Hlavacka F (2008). Age-related changes of human balance during quiet stance. Physiol Res, 57: 957-964.
[35] Wang Y, Magasi S, Bohannon R, Reuben D, McCreath H, Bubela D, et al. (2011). Assessing dexterity function: a comparison of two alternatives for the NIH Toolbox. J Hand Ther, 24: 313-320.
[36] Signore P, Chaoui M, Nosten-Bertrand M, Perez-Diaz F, Marchaland C (1991). Handedness in mice: comparison across eleven inbred strains. Behav Genet, 21: 421-429.
[37] Luong T, Carlisle H, Southwell A, Patterson P (2011). Assessment of motor balance and coordination in mice using the balance beam. J Vis Exp, 49: 2376.
[38] Deacon R (2013). Measuring motor coordination in mice. J Vis Exp, 75: 2609.
[39] McGee M, Weber D, Day N, Vitell iC, Crippen D, Herndon L, et al. (2011). Loss of intestinal nuclei and intestinal integrity in aging C. elegans. Aging Cell, 10: 699-710.
[40] Fragala M, Kenny A, Kuchel G (2015). Muscle quality in aging: a multi-dimensional approach to muscle functioning with applications for treatment. Sports Med, 45: 641-658.
[41] Cao Z, Wu Y, Curry K, Wu Z, Christen Y, Luo Y (2007). Ginkgo biloba extract EGb 761 and Wisconsin Ginseng delay sarcopenia in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci, 62: 1337-1345.
[42] Iwasa H, Yu S, Xue J, Driscoll M (2010). Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation. Aging Cell, 9(4): 490-505.
[43] Sutphin G, Backer G, Sheehan S, Bean S, Corban C, Liu T, et al. (2017). Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging cell, 16: 672-682.
[44] Deacon R (2013). Measuring the strength of mice. J Vis Exp, 76: 2610.
[45] Viken H, Reitlo LS, Zisko N, Nauman J, Aspvik NP, Ingebrigtsen JE, et al. (2018). Predictors of Dropout in Exercise Trials in Older Adults. Med Sci Sports Exerc.
[46] Nguyen TT, Caito SW, Zackert WE, West JD, Zhu S, Aschner M, et al. (2016). Scavengers of reactive gamma-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. Aging, 8: 1759-1780.
[47] Jafari M (2015). Healthspan Pharmacology. Rejuvenation Res, 18: 573-580.
[48] Peel N, Kuys S, Klein K (2013). Gait speed as a measure in geriatric assessment in clinical settings: a systematic review. J Gerontol A Biol Sci Med Sci, 68: 39-46.
[49] Broom L, Ellison B, Worley A, Wagenaar L, Sörberg E, Ashton C, et al. (2017). A translational approach to capture gait signatures of neurological disorders in mice and humans. Scientific reports, 7: 3225.
[50] Bazopoulou D, Chaudhury A, Pantazis A, Chronis N (2017). An automated compound screening for anti-aging effects on the function of C. elegans sensory neurons. Scientific reports, 7: 9403.
[51] Brown M, Evans J, Luo Y (2006). Beneficial effects of natural antioxidants EGCG and alpha-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditis elegans. Pharmacol Biochem Behav, 85: 620-628.
[52] Schubert CR, Carmichael LL, Murphy C, Klein BE, Klein R, Cruickshanks KJ (2008). Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc, 56: 1517-1521.
[53] Sarter M (1987). Measurement of cognitive abilities in senescent animals. Int J Neurosci, 32: 765-774.
[54] Gallagher M, Stocker A, Koh M (2011). Mindspan: lessons from rat models of neurocognitive aging. ILAR journal / National Research Council, Institute of Laboratory Animal Resources, 52: 32-40.
[55] Spiegel A, Sewal A, Rapp P (2014). Epigenetic contributions to cognitive aging: disentangling mindspan and lifespan. Learn Mem, 21: 569-574.
[56] Kauffman A, Ashraf J, Corces-Zimmerman M, Landis J, Murphy C (2010). Insulin signaling and dietary restriction differentially influence the decline of learning and memory with age. PLoS biology, 8: e1000372.
[57] Hood S, Amir S (2017). The aging clock: circadian rhythms and later life. J Clin Invest, 127: 437-446.
[58] Bizon J, Foster T, Alexander G, Glisky E (2012). Characterizing cognitive aging of working memory and executive function in animal models. Front Aging Neurosci, 4: 19.
[59] Salthouse T (2010). Selective review of cognitive aging. J Int Neuropsychol Soc, 16: 754-760.
[60] Chen X, Barclay J, Burgoyne R, Morgan A (2015). Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. Chem Cent J, 9: 65.
[61] Hughes S, Evason K, Xiong C, Kornfeld K (2007). Genetic and pharmacological factors that influence reproductive aging in nematodes. PLoS genetics, 3: e25.
[62] Honda Y, Tanaka M, Honda S (2010). Trehalose extends longevity in the nematode Caenorhabditis elegans. Aging Cell, 9: 558-569.
[63] Zhang Y, Mi D, Wang J, Luo Y, Yang X, Dong S, et al. (2018). Constituent and effects of polysaccharides isolated from Sophora moorcroftiana seeds on lifespan, reproduction, stress resistance, and antimicrobial capacity in Caenorhabditis elegans. Chin J Nat Med, 16: 252-260.
[64] Zietsch BP, Kuja-Halkola R, Walum H, Verweij KJ (2014). Perfect genetic correlation between number of offspring and grandoffspring in an industrialized human population. Proc Natl Acad Sci U S A, 111: 1032-1036.
[65] Evason K, Huang C, Yamben I, Covey D, Kornfeld K (2005). Anticonvulsant medications extend worm life-span. Science, 307: 258-262.
[66] Biks GA, Tariku A, Wassie MM, Derso T (2018). Mother's Infant and Young Child Feeding (IYCF) knowledge improved timely initiation of complementary feeding of children aged 6-24 months in the rural population of northwest Ethiopia. BMC Res Notes, 11: 593.
[67] Fried L, Tangen C, Walston J, Newman A, Hirsch C, Gottdiener J, et al. (2001). Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci, 56: M146-M156.
[68] Rockwood K, Mitnitski A (2007). Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci, 62: 722-727.
[69] Sanders J, Minster R, Barmada M, Matteini A, Boudreau R, Christensen K, et al. (2014). Heritability of and mortality prediction with a longevity phenotype: the healthy aging index. J Gerontol A Biol Sci Med Sci, 69: 479-485.
[70] Tyrovolas S, Haro J, Mariolis A, Piscopo S, Valacchi G, Tsakountakis N, et al. (2014). Successful aging, dietary habits and health status of elderly individuals: a k-dimensional approach within the multi-national MEDIS study. Experimental gerontology, 60: 57-63.
[71] Jaspers L, Schoufour J, Erler N, Darweesh S, Portegies M, Sedaghat S, et al. (2017). Development of a Healthy Aging Score in the Population-Based Rotterdam Study: Evaluating Age and Sex Differences. J Am Med Dir Assoc, 18:276.e271-276.e277.
[72] Seeman T, McEwen BS, Rowe JW, Singer B (2001). Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proceedings of the National Academy of Sciences of the United States of America, 98: 4770-4775.
[73] Li Q, Wang S, Milot E, Bergeron P, Ferrucci L, Fried L, et al. (2015). Homeostatic dysregulation proceeds in parallel in multiple physiological systems. Aging cell, 14: 1103-1112.
[74] Cohen A, Milot E, Yong J, Seplaki C, Fülöp T, Bandeen-Roche K, et al. (2013). A novel statistical approach shows evidence for multi-system physiological dysregulation during aging. Mechanisms of ageing and development, 1334: 110-117.
[75] Panuganti K, Dulebohn S 2017. Transient Ischemic Attack. In StatPearls. www.ncbi.nlm.nih.gov/books/NBK459143/.
[76] Giovannoni G (2017). The neurodegenerative prodrome in multiple sclerosis. Lancet Neurol, 16: 413-414.
[77] Erikson GA, Bodian DL, Rueda M, Molparia B, Scott ER, Scott-Van Zeeland AA, et al. (2016). Whole-Genome Sequencing of a Healthy Aging Cohort. Cell, 165: 1002-1011.
[78] D'Amico D, Sansone E, Grazzi L, Giovannetti AM, Leonardi M, Schiavolin S, et al. (2018). Multimorbidity in patients with chronic migraine and medication overuse headache. Acta Neurol Scand.
[79] Cesari M, Araujo de Carvalho I, Amuthavalli Thiyagarajan J, Cooper C, Martin F, Reginster J, et al. (2018). Evidence for The Domains Supporting The Construct of Intrinsic Capacity. J Gerontol A Biol Sci Med Sci, [Epub ahead of print].
[80] Kritchevsky S, Forman D, Callahan K, Ely E, High K, McFarland F, et al. (2018). Pathways, Contributors, and Correlates of Functional Limitation across Specialties: Workshop Summary. J Gerontol A Biol Sci Med Sci, [Epub ahead of print].
[81] Panza F, Solfrizzi V, Barulli M, Santamato A, Seripa D, Pilotto A, et al. (2015). Cognitive Frailty: A Systematic Review of Epidemiological and Neurobiological Evidence of an Age-Related Clinical Condition. Rejuvenation Res, 18: 389-412.
[82] Brown R, Covinsky K (2018). Frailty as an Outcome in Geriatrics Research: Not Ready for Prime Time? Ann Intern Med, 168: 361-362.
[83] Michel J-P, Sadana R (2017). "Healthy aging": concepts and measures. J Am Med Dir Assoc, 18: 460-464.
[84] Mamoshina P, Kochetov K, Putin E, Cortese F, Aliper A, Lee W, et al. (2018). Population specific biomarkers of human aging: a big data study using South Korean, Canadian and Eastern European patient populations. J Gerontol A Biol Sci Med Sci, [Epub ahead of print].
[85] Murabito J, Zhao Q, Larson M, Rong J, Lin H, Benjamin E, et al. (2017). Measures of biological age in a community sample predict mortality and age-related disease: the Framingham Offspring Study. J Gerontol A Biol Sci Med Sci, 73: 757-762.
[86] O'Connell M, Marron M, Boudreau R, Canney M, Sanders J, Kenny R, et al. (2018). Mortality in Relation to Changes in a Healthy Aging Index: The Health, Aging and Body Composition Study. J Gerontol A Biol Sci Med Sci, [Epub ahead of print].
[87] de la Fuente J, Caballero F, Sanchez-Niubo A, Panagiotakos D, Prina A, Arndt H, et al. (2018). Determinants of health trajectories in England and the United States: an approach to identify different patterns of healthy aging. J Gerontol A Biol Sci Med Sci, DOI: .
doi: 10.1093/gerona/gly006
[88] Wei M, Kabeto M, Langa K, Mukamal K (2018). Multimorbidity and Physical and Cognitive Function: Performance of a New Multimorbidity-Weighted Index. J Gerontol A Biol Sci Med Sci, 73: 225-232.
[89] Rodriguez-Laso A, McLaughlin S, Urdaneta E, Yanguas J (2018). Defining and estimating healthy aging in Spain: a cross-sectional study. Gerontologist, 58: 388-398.
[90] Escorpizo R, Kostanjsek N, Kennedy C, Nicol M, Stucki G, Ustün T (2013). Harmonizing WHO's International Classification of Diseases (ICD) and International Classification of Functioning, Disability and Health (ICF): importance and methods to link disease and functioning. BMC Public Health, 13: 742.
[91] McMurry J, Köhler S, Washington NL, Balhoff J, Borromeo C, Brush M, et al. (2016). Navigating the Phenotype Frontier: The Monarch Initiative. Genetics, 203: 1491-1495.
[92] Faragher R (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. Front Genet, 6: 171.
[93] Timmons JA (2017). Molecular Diagnostics of Ageing and Tackling Age-related Disease. Trends in pharmacological sciences, 38: 67-80.
[94] Stambler I (2017). Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy. Aging and disease, 8: 583-589.
[95] Group BDW (2001). Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther, 69: 89-95.
[96] Levine ME (2013). Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age? The journals of gerontology. Series A, Biological sciences and medical sciences, 68: 667-674.
[97] Jylhava J, Pedersen NL, Hagg S (2017). Biological Age Predictors. EBioMedicine, 21: 29-36.
[98] Moeller M, Hirose M, Mueller S, Roolf C, Baltrusch S, Ibrahim S, et al. (2014). Inbred mouse strains reveal biomarkers that are pro-longevity, antilongevity or role switching. Aging cell, 13: 729-738.
[99] Arntzenius F 2010. Reichenbach's Common Cause Principle. In The Stanford Ency-clopedia of Philosophy (Fall 2010 Edition). Zalta E, editor. https://plato.stanford.edu/archives/fall2010/entries/physics-Rpcc/.
[100] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013). The hallmarks of aging. Cell, 153: 1194-1217.
[101] Franceschi C, Campisi J (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci, 69: S4-S9.
[102] Gavrilov L, Gavrilova N (2001). The reliability theory of aging and longevity. J Theor Biol, 213: 527-545.
[103] Moeller M, Pink C, Endlich N, Endlich K, Grabe HJ, Volzke H, et al. (2017). Mortality is associated with inflammation, anemia, specific diseases and treatments, and molecular markers. PLoS One, 12: e0175909.
[104] Fuellen G, Jansen L, Leser U, Kurtz A (2013). Using ontologies to study cell transitions. Journal of biomedical semantics, 4: 25.
[105] Gavrilov LA, Gavrilova NS 2006. Reliability Theory of Aging and Longevity. In Handbook of the Biology of Aging, Sicth Edition: Academic Press. 3-15.
[106] Blagosklonny M (2008). Aging: ROS or TOR. Cell Cycle, 7: 3344.
[107] Gladyshev V (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging cell, 15: 594-602.
[108] Fischer KE, Gelfond JA, Soto VY, Han C, Someya S, Richardson A, et al. (2015). Health Effects of Long-Term Rapamycin Treatment: The Impact on Mouse Health of Enteric Rapamycin Treatment from Four Months of Age throughout Life. PLoS One, 10: e0126644.
[109] Williams G (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution, 11: 398-411.
[110] Luyten W, Antal P, Braeckman BP, Bundy J, Cirulli F, Fang-Yen C, et al. (2016). Ageing with elegans: a research proposal to map healthspan pathways. Biogerontology, 17: 771-782.
[111] Kanehisa M, Goto S (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic acids research, 28: 27-30.
[112] Moeller S, Saul N, Cohen A, Koehling R, Sender S, Murua Escobar H, et al. (2018). Healthspan pathway maps in C. elegans and humans highlight transcription, prolifera-tion/biosynthesis and lipids. BioRxiv, doi: .
doi: 10.1101/355131
[113] Zierer J, Pallister T, Tsai P, Krumsiek J, Bell J, Lauc G, et al. (2016). Exploring the molecular basis of age-related disease comorbidities using a multi-omics graphical model. Sci Rep, 6: 37646.
[114] Agarwal A, Fryns J, Auchus R, Garg A (2003). Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet, 12: 1995-2001.
[115] Ahmad Z, Zackai E, Medne L, Garg A (2010). Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24. Am J Med Genet A, 152(A): 2703-2710.
[116] Takenouchi T, Hida M, Sakamoto Y, Torii C, Kosaki R, Takahashi T, et al. (2013). Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype. Am J Med Genet A, 161(A): 3057-3062.
[117] WHO. 2015. World report on ageing and health. www.who.int/ageing/events/world-report-2015-launch/en/.
[118] Ziegelstein R (2017). Personomics: The Missing Link in the Evolution from Precision Medicine to Personalized Medicine. J Pers Med, 7: pii:E11.
[119] Bulterijs S, Hull RS, Bjork VC, Roy AG (2015). It is time to classify biological aging as a disease. Front Genet, 6: 205.
[120] Lakatta EG (2015). So! What's aging? Is cardiovascular aging a disease? J Mol Cell Cardiol, 83: 1-13.
[121] Gavrilov LA, Gavrilova NS (2017). Is Aging a Disease? Biodemographers’ Point of View. Adv Gerontol, 30: 841-842.
[122] Hughes B, Hekimi S (2016). Different Mechanisms of Longevity in Long-Lived Mouse and Caenorhabditis elegans Mutants Revealed by Statistical Analysis of Mortality Rates. Genetics, 204: 905-920.
[123] Jansen L2018. Functions, malfunctioning, and negative causation. In Philosophy of Science - Between the Natural Sciences, the Social Sciences, and the Humanities. Christian A, Hommen D, Retzlaff N, and Schurz G, editors: Springer Cham. 117-135.
[1] Xu Dingqiao, Liao Shanting, Li Pei, Zhang Qian, Lv Yan, Fu Xiaowei, Yang Minghua, Wang Junsong, Kong Lingyi. Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis[J]. Aging and disease, 2019, 10(4): 854-870.
[2] Wang Min-jun, Chen Jiajia, Chen Fei, Liu Qinggui, Sun Yu, Yan Chen, Yang Tao, Bao Yiwen, Hu Yi-Ping. Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging[J]. Aging and disease, 2019, 10(4): 871-882.
[3] Cho Kyoungjoo. Emerging Roles of Complement Protein C1q in Neurodegeneration[J]. Aging and disease, 2019, 10(3): 652-663.
[4] Gourmelon Robin, Donadio-Andréi Sandrine, Chikh Karim, Rabilloud Muriel, Kuczewski Elisabetta, Gauchez Anne-Sophie, Charrié Anne, Brard Pierre-Yves, Andréani Raphaëlle, Bourre Jean-Cyril, Waterlot Christine, Guédel Domitille, Mayer Anne, Disse Emmanuel, Thivolet Charles, Boullay Hélène Du, Falandry Claire, Gilbert Thomas, François-Joubert Anne, Vignoles Antoine, Ronin Catherine, Bonnefoy Marc. Subclinical Hypothyroidism: is it Really Subclinical with Aging?[J]. Aging and disease, 2019, 10(3): 520-529.
[5] Jin Kunlin. A Microcirculatory Theory of Aging[J]. Aging and disease, 2019, 10(3): 676-683.
[6] Chung Hae Young, Kim Dae Hyun, Lee Eun Kyeong, Chung Ki Wung, Chung Sangwoon, Lee Bonggi, Seo Arnold Y., Chung Jae Heun, Jung Young Suk, Im Eunok, Lee Jaewon, Kim Nam Deuk, Choi Yeon Ja, Im Dong Soon, Yu Byung Pal. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept[J]. Aging and disease, 2019, 10(2): 367-382.
[7] Sarkar Saumyendra N., Russell Ashley E., Engler-Chiurazzi Elizabeth B., Porter Keyana N., Simpkins James W.. MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma[J]. Aging and disease, 2019, 10(2): 329-352.
[8] Cyprien Fabienne, Courtet Philippe, Maller Jerome, Meslin Chantal, Ritchie Karen, Ancelin Marie-Laure, Artero Sylvaine. Increased Serum C-reactive Protein and Corpus Callosum Alterations in Older Adults[J]. Aging and disease, 2019, 10(2): 463-469.
[9] Lana Alberto, Struijk Ellen A., Arias-Fernandez Lucía, Graciani Auxiliadora, Mesas Arthur E., Rodriguez-Artalejo Fernando, Lopez-Garcia Esther. Habitual Meat Consumption and Changes in Sleep Duration and Quality in Older Adults[J]. Aging and disease, 2019, 10(2): 267-277.
[10] Murtha Lucy A., Morten Matthew, Schuliga Michael J., Mabotuwana Nishani S., Hardy Sean A., Waters David W., Burgess Janette K., Ngo Doan TM., Sverdlov Aaron L., Knight Darryl A., Boyle Andrew J.. The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis[J]. Aging and disease, 2019, 10(2): 419-428.
[11] Calvo Ana C., Cibreiro Gabriela Atencia, Merino Paz Torre, Roy Juan F., Galiana Adrián, Rufián Alexandra Juárez, Cano Juan M., Martín Miguel A., Moreno Laura, Larrodé Pilar, Vázquez Pilar Cordero, Galán Lucía, Mora Jesús, Muñoz-Blanco José L., Muñoz María J., Zaragoza Pilar, Pegoraro Elena, Sorarù Gianni, Mora Marina, Lunetta Christian, Penco Silvana, Tarlarini Claudia, Esteban Jesús, Osta Rosario, Redondo Alberto García. Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis[J]. Aging and disease, 2019, 10(2): 278-292.
[12] Shetty Ashok K., Upadhya Raghavendra, Madhu Leelavathi N., Kodali Maheedhar. Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 470-482.
[13] Tingting Sui,Di Liu,Tingjun Liu,Jichao Deng,Mao Chen,Yuanyuan Xu,Yuning Song,Hongsheng Ouyang,Liangxue Lai,Zhanjun Li. LMNA-mutated Rabbits: A Model of Premature Aging Syndrome with Muscular Dystrophy and Dilated Cardiomyopathy[J]. Aging and disease, 2019, 10(1): 102-115.
[14] Poyin Huang,Cheng-Sheng Chen,Yuan-Han Yang,Mei-Chuan Chou,Ya-Hsuan Chang,Chiou-Lian Lai,Hsuan-Yu Chen,Ching-Kuan Liu. REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer’s Disease[J]. Aging and disease, 2019, 10(1): 94-101.
[15] Dong Liu,Liqun Xu,Xiaoyan Zhang,Changhong Shi,Shubin Qiao,Zhiqiang Ma,Jiansong Yuan. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury[J]. Aging and disease, 2019, 10(1): 116-133.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd