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1 Presubmission publication, request for comments:

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3

4 Classifying Aging as a Disease in the context of ICD-11

5

Alex Zhavoronkov1,2*

, Bhupinder Bhullar3 6

7

1 8 The Biogerontology Research Foundation, Oxford, United Kingdom

2 9 Insilico Medicine, Johns Hopkins University, Emerging Technology Centers, Baltimore, MD,

10 21218, USA

3 11 Novartis Pharma AG, Department of Developmental and Molecular Pathways, Novartis

12 Institute for Biomedical Research, Fabrikstrasse 22, 4056 Basel, Switzerland

13

14 *Alex Zhavoronkov, PhD, +1 626 593 7957, [email protected]

15

16 Abstract

17

18 Aging is a complex continuous multifactorial process leading to loss of function and crystalizing

19 into the many age-related diseases. Here, we explore the arguments for classifying aging as a

20 disease in the context of the upcoming World Health Organization’s 11th International Statistical

21 Classification of Diseases and Related Health Problems (ICD-11), expected to be finalized in

22 2018. We hypothesize that classifying aging as a disease will result in new approaches and

23 business models for addressing aging as a treatable condition, which will lead to both economic

24 and healthcare benefits for all stakeholders. Classification of aging as a disease may lead to more

25 efficient allocation of resources by enabling funding bodies and other stakeholders to use

26 quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when

27 evaluating both research and clinical programs. We propose forming a Task Force to interface

28 the WHO in order to develop a multidisciplinary framework for classifying aging as a disease.

29

30 Introduction

31

32 The recognition of a condition or a chronic process as a disease is an important milestone for the

33 pharmaceutical industry, academic community, healthcare and insurance companies, policy

34 makers, and individual, as the presence of a condition in disease nomenclature and classification

35 greatly impacts the way it is treated, researched and reimbursed. However, achieving a

36 satisfactory definition of disease is challenging, primarily due to the vague definitions of the

37 state of health and disease. Here, we explore the potential benefits of recognizing aging as a

38 disease in the context of current socioeconomic challenges and recent biomedical advances.

39

40 Brief History of Disease Classification

41

42 The concept of disease classification has existed for centuries, with professional classification

dating back to 15th 43 century Italy, but international classification systems were not established

44 until relatively recently. One of the first major strides was made by William Cullen, who

45 provided a classified list of diseases in his Nosolagae Methodicae synopsis in 1769. The first

46 authoritative sources of disease terminology were then developed in 19th century England

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47 (Robb-smith 1969; Moriyama et al., 2011), followed by the nomenclature of diseases by the

48 American Medical Association (National Conference on Nomenclature of Disease, 1933;

49 American Medical Association, 1961). Real progress toward the modern classification system,

50 however, began when efforts were internationalized. The first international nomenclature and

51 disease classification was created and maintained by the International Statistical Institute (ISI)

52 and is generally referred to as ICD-1, as it was developed at the first international conference to

53 revise the International Classification of Causes of Death in 1900. Since 1948, the World Health

54 Organization (WHO) has assumed the responsibility of maintaining, preparing and publishing

55 the revisions of the ICD. The 10th revision of the ICD, referred as ICD-10, was first published in

56 1992 (World Health Organization, 1992), and the 11th revision (ICD-11) is expected to be

57 released in 2018 (http://www.who.int/classifications/icd/revision/timeline/en/). Thus, as this date

58 approaches there is a sense of urgency among all stakeholders to codify classification proposals

59 before the window of opportunity closes for another decade or longer (World Health

60 Organization, 2006).

61

62 In its current definition, published in 1948, WHO describes health as a “state of complete

63 physical, mental and social well-being, not merely the absence of infirmity” (World Health

64 Organization, 1948). This definition is restrictive and there have been an increasing number of

65 calls to change it (Saracci, 1997;Bircher, 2005;Huber et al., 2011). The criteria for disease, on

66 the other hand, have historically changed over time. This is partly due to increasing health

67 expectations or changes in diagnostic abilities, but mostly due to a combination of social and

68 economic reasons (Scully, 2004). It was not until the 6th revision of ICD (ICD-6) in 1949 that

69 mental disorders were first classified as diseases (Katschnig, 2010). On the other extreme,

70 homosexuality was classified as a disease until 1974 by the American Psychiatric Association

71 (APA) (Reznek, 1987), an organization which frequently disagrees with the ICD on disease

72 classification. Since the completion of ICD-10, debates in biomedical literature have been

73 primarily focused on psychiatric disorders (First et al., 2015). A recent PubMed search using

74 “ICD-11” since 1992 produced 333 results, while “’ICD-11’ NOT mental NOT psychiatric”

75 produced only 61 results.

76

77 While mental health issues continue to stay at the forefront, another major socioeconomic

78 problem has surfaced and is here to stay. Over the past decade, there has been an enormous shift

79 in the percentage of the world population that is elderly, and age demographics are projected to

80 continue to change dramatically in this direction in the next few decades. The socioeconomic

81 burden of this shift cannot be understated. Without advances in the ability to slow the aging

82 process, extend the healthy life span, and prevent the associated diseases, it will be difficult to

83 support the large numbers of those no longer enrolled in the workforce and instead enrolled in

84 costly long term health care.

85

86 Fortunately, the ability to track multiple underlying causes of death has provided a more granular

87 view on the causes of death in old age and in turn has facilitated better disease association and

88 classification (Moriyama et al., 2011). Our understanding of aging mechanisms is constantly

89 evolving. Similarly, disease classification is an evolving process and advances in our

90 understanding of aging may enable the classification of aging as a disease in the upcoming

91 revision of the ICD. To do so would have multiple benefits, garner more attention on the topic,

92 and ultimately boost progress in this active area of biomedical research.

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93

94 Biology of aging as a disease

95

96 Aging is a complex multifactorial process leading to loss of function, multiple diseases, and

97 ultimately death. There are many theories explaining the origin of the overall process (Lopez-

98 Otin et al., 2013;Deleidi et al., 2015), cause and effect relationships between different processes

99 and systems, including aging of the immune system (Montecino-Rodriguez et al., 2013),

100 inflammation (Bruunsgaard et al., 2001;Sarkar and Fisher, 2006;Franceschi et al., 2007;Michaud

101 et al., 2013), fibrosis (Cieslik et al., 2011;Kapetanaki et al., 2013), mineralization of connective

102 tissue (Shindyapina et al., 2014), cellular senescence (van Deursen, 2014), wear and tear, and

103 many others. In addition, many genetic and epigenetic changes implicated in aging and longevity

104 are associated with aging in model organisms (Lombard et al., 2005;Moskalev et al., 2014). Even

105 though their role and action in human aging are uncertain, many of these changes are also

106 associated with human diseases (Kennedy et al., 2015; Aguilar-Olivos et al., 2015;De Rosa et al.,

107 2015;Helling and Yang, 2015;Lardenoije et al., 2015;Renauer et al., 2015). Recent discoveries

108 showing that mechanisms involved in cancer are also associated with the aging process have led

109 to multiple proposals to prevent cancer and other age-related diseases using drugs that increase

110 lifespan in model organisms (Blagosklonny, 2013;Zhavoronkov et al., 2014).

111

112 Surprisingly, aging shares many characteristics with Human Immunodeficiency Virus (HIV), as

113 while having a specific ICD-10 code, HIV is the cause of many fatal diseases associated with a

114 broad range of ICD-10 codes. However, unlike HIV, classifying aging as a disease is difficult

115 because of the absence of a clear set of aging biomarkers and the uncertainty of the time of

116 transition from loss of function to disease. There is some progress in this area; recent population

117 statistics and studies clearly demonstrate the relationship of aging and increased risk of multiple

118 diseases (Marengoni et al., 2011;Federal Interagency Forum on Aging-Related Statistics,

119 2012;Salive, 2013), and there are several frailty indexes that measure the rate of physical decline

120 and sets of aging biomarkers (Moreno-Villanueva et al.;Horvath, 2013). However, the transition

121 from aging to disease remains unclear both at the individual and population levels (Figure 1).

122

123 Public opinion and stakeholders’ views on aging as a disease

124

125 At the start of the twentieth century, most causes of death in advanced age were attributed to “old

126 age” and “natural causes” (Moriyama et al., 2011). However, over the course of the twentieth

127 century, the understanding of aging and disease changed (Shock et al., 1984;Bulterijs et al.,

128 2015;Faragher, 2015), with many age-related diseases and causes of death being clearly defined

129 (Vellas et al., 1992). Over time, many chronic diseases of old age previously considered to be a

130 part of normal aging including hypertension, rheumatoid arthritis, cardiomyopathy, and

131 osteoporosis received classification codes (Bennett et al., 1956;force, 1980;WHO, 1994).

132 Historically, “old age” was among the acceptable causes of death and was used on death

133 certificates (Moriyama et al., 2011). Most countries now provide guidelines limiting the use of

134 the term on medical certificates by age and issuing recommendations to avoid using only “old

135 age” as a cause of death (Office for National Statistics, 2010), since “terms such as senescence,

136 infirmity, old age, and advanced age have little value for public health or medical research“

137 (Centers for Disease Control, 2004). The same arguments are commonly used in debates against

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138 classifying aging as a disease, as many stakeholders would prefer to have a more granular view

139 into causes of death.

140

141 To illustrate these differences in opinion about aging, a recent survey in Finland assessed

142 stakeholders’ perspectives on what constitutes a disease. The study surveyed 3,000 laypeople,

143 1,500 doctors, 1,500 nurses and 200 parliament members and asked them to rate 60 “states of

144 being” by their perception of disease. And while most cancers like breast cancer (#1) and

145 prostate cancer (#2) were clearly classified as diseases, wrinkles (#60), smoking (#59) and

146 ageing (#58) were not classified as diseases (Tikkinen et al., 2012). Most of the doctors and

147 nurses did not consider sarcopenia, age-related muscle loss (#31) as a disease. Surprisingly,

148 obesity (#50), was not considered to be a disease by any of the stakeholder groups even though it

149 is now classified as a disease with multiple disease codes (E65-E68) in endocrine, nutritional and

150 metabolic diseases (E00-E90), representing a considerable part of chapter IV in ICD-10 (World

151 Health Organization, 2011). The case of obesity provides clues that the opinion of multiple

152 stakeholders including medical, general public, doctors and nurses may deviate from the WHO

153 consensus for the purposes of disease classification, and other stakeholders may play a larger

154 role in forming ICD revisions.

155

156 In another survey of pension funds, insurance companies, and employee benefits industries; only

157 11% of respondents felt that aging is a disease and less than 22% used simulations involving

158 biomedical advances in forecasting life expectancy (Zhavoronkov, 2015). Considering the

159 relatively conservative responses, these stakeholder groups may not be in favor of classifying

160 aging as a disease in the ICD-11 revision.

161

162 The debate on whether aging should be classified as a disease is taking place primarily in

163 academic circles (Ries, 1976;Glasser, 1986;Williams, 1987;Blumenthal, 1993;Callahan and

164 Topinkova, 1998;Blumenthal, 2003;Faragher, 2015;Gems, 2015b) with no consensus opinion

165 (Garber, 2008;Donmez and Guarente, 2010) and even some opposing views from

166 biogerontologists (Ardeljan and Chan, 2013;Rattan, 2014). Even though some of these views aim

167 at higher citation rating or other objectives, these opposing views do not propose concrete plans

168 for addressing the aging problem at the level of WHO.

169

170 Prior history with many mental disorders, including autism (Lord and Jones, 2012), demonstrates

171 that classifying a state of being as a disease leads to an increased attention to the subject, the

172 development of more accurate diagnostic methods, and increased involvement of the

173 pharmaceutical industry and policy makers. It also provides the basis for clinical trials.

174

175 Strategies in moving forward

176

177 Large scale studies in humans. There are many strategies that can be pursued to test the efficacy

178 of geroprotectors in humans, including large scale publicly-funded supplement studies and

179 studies designed to address a specific set of biomarkers of aging (Hefti and Bales, 2006;Le

180 Couteur et al., 2012;Scott and DeFrancesco, 2015). The results from the Novartis RAD001 study

181 in healthy elderly patients as a vaccine-potentiating agent (Mannick et al., 2014) elucidated the

182 possibility of ameliorating immunosenescence in the elderly and raises the prospect of delaying

183 the onset of age-related diseases.

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184

185 Aging biomarkers. Even though major advances have been made since the final ICD-10 meeting

186 in tracking aging at all levels of organization (Sprott, 2010;Le Couteur et al., 2012;Hatse et al.,

187 2014;Wu et al., 2015), there is no universal set of biomarkers and guidelines for measuring aging

188 as a system. However, in order to successfully evaluate the effect of any drug that influences

189 aging, it is essential have a measureable endpoint, such as biomarkers. Gerontologists have

190 previously struggled to extrapolate biomarkers from animal models to humans (Butler et al.,

191 2004). But with the advent of Big Data, it is now possible to track aging on the epigenetic level

192 and measure accelerated aging in many diseases (Horvath et al., 2014;Horvath and Levine,

193 2015). There are also promising studies of transcriptomic (Nakamura et al., 2012;Dhahbi, 2014),

194 telomere-length (Zhang et al., 2014;Shamir, 2015) and multi-variate (Sanders et al., 2014) blood-

195 based biomarkers that may lead to minimally invasive diagnostic tests. It is also possible to track

196 signalome-level biomarkers . Recent studies have shown that signaling pathways found in aging

197 are comparable to and share many characteristics with Hutchinson-Gilford Progeria Syndrome

198 (HGPS) (Aliper et al., 2015) and Age-related Macular Degeneration (AMD) (Makarev et al.,

199 2014). It is also possible to use system-wide biomarkers like heart rate variability (HRV) as

200 biomarkers of aging (Corino et al., 2007). There is a rapidly growing body of evidence that

201 biomarkers of aging contributes and is very similar to the many age-related diseases on all levels

202 of organization and it is possible to multiplex epigenetic, transcriptomic, proteomic, signalomic,

203 metabolomic, metagenomic and phenotypic biomarkers to track the progression of aging as a

204 disease.

205

206 Since the transition from age-associated processes to disease is unclear (Figure 1), in the absence

207 of readily available and highly personalized biomarkers, one of the approaches to set the gold

208 standard for health, is to select the age when peak performance is observed in the majority of the

209 population. There are conflicting theories without convincing empirical evidence that the human

210 skeleton stops growing at approximately the age of 20 (Nilsson et al., 2005). Peak age for

211 athletic performance depends upon sports disciplines and is usually in the range of 20-30 years

212 with younger age of peak performance in short distance races and gradually increasing age of

213 peak performance in longer racing distances (Elmenshawy et al., 2015). In prenatal diagnostics,

214 statistics for Down’s and other chromosomal abnormalities led to recommendations for invasive

215 prenatal screening after 35, which is generally referred to as advanced maternal age, procedures

216 that have gradually been replaced by non-invasive prenatal procedures. (Chiu et al., 2009;Nakata

217 et al., 2010;Benn et al., 2013;Lo, 2013;Nepomnyashchaya et al., 2013;Twiss et al.,

218 2014;Neufeld-Kaiser et al., 2015).

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220

221 Figure 1: Gradual transition from the loss of function and homeostasis due to aging into age-

222 related pathologies. It is clear that with time the combination of many age-related processes

223 becomes more granular and crystallizes into specific diseases. However, it is unclear when aging

224 starts and when the transition between aging and pathology occurs.

225

226 Discussion

227

228 Many scientists throughout the world have argued that aging should be classified as a disease

229 (Bulterijs et al., 2015;Gems, 2015a). The recent decision of the Food and Drug Administration

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230 (FDA) to test the potential of metformin in reducing risk of developing age-related conditions

231 including cancer, heart disease and cognitive impairment resonated in the community, increased

232 attention to the field, and suggested that aging may be an indication appropriate for clinical trials

233 (Check Hayden, 2015). However, there are no visible global or national efforts to include aging

234 in the ICD-11 classification as a disease. This is primarily due to the structure and clear

235 separation of the supplement and wellness markets and disease treatment markets. Stakeholders

236 in the wellness market are selling billions of dollars worth of goods and services and are not

237 interested in increased regulation. Also, the structure of the supplement market, where large

238 ingredient vendors supply product to compounders that in turn supply brand holders that sell

239 through distribution networks, does not provide incentives or ability at any level to engage in

240 discussions with policy makers.

241

242 As demonstrated in Figure 1, individual consumers of healthcare cannot formulate the demand

243 for evidence-based medicine (pharmaceuticals) to combat aging and rely on the less-regulated

244 wellness and alternative medicine industry. The fact that the supplement industry is prosperous,

245 with a total estimated sale of $36.7 billion in the US in 2014, implies that there is consumer

246 demand for anti-aging treatments (Nutrition Business Journal, 2015). Increasing regulation of the

247 supplements and wellness industry may lead to more demand and a supply of evidence-based

248 approaches to interventions in aging.

249

250 Increasing productive longevity in the developed countries is likely to reduce healthcare costs,

251 boost employee productivity and lead to substantial economic growth (Zhavoronkov and

252 Litovchenko, 2013), while the inability to increase productive longevity quickly may result in

253 economic collapse (Zhavoronkov et al., 2012). Yet when it comes to aging, policy makers, the

254 general public, and even pension funds lack the sense of urgency to address it as a curable

255 disease (Zhavoronkov, 2015) even though there is a growing realization of the likely economic

256 problems (Zhavoronkov, 2013). Even some of the most reputable demographers, gerontologists

257 and biogerontologists express conflicting opinions on the subject, providing arguments against

258 classifying aging as a disease. While these papers promote debate and increase their citation

259 ratings, they are certainly not helpful for making the case for formal classification of aging as a

260 disease or family of diseases. Formal classification of aging as a disease is likely to unite both

261 scientists and medical practitioners in this effort.

262

263 There are also ethical considerations associated with classifying aging as a disease (Caplan,

264 2005). A large portion of the population may feel uncomfortable with the idea and resist being

265 classified as disease carriers either at birth or after a specific age certain age while lacking clear

266 representation of a disease. However, the recent inclusion of obesity in ICD-10 has shown that it

267 not only helped to attract resources to research, but it also resulted in more frequent diagnosis of

268 the condition. Since obesity has been classified as a disease, it is now easier for medical

269 practitioners to convince patients to pursue healthier lifestyles and prescribe medication, even in

270 cases where patients are comfortable with the condition.

271

272 Recommendations for Implementation

273

274 Form a task force. As part of the upcoming ICD-11, the International Association for the Study

275 of Pain (IASP) Task Force was created to classify chronic pain as a disease (Treede et al., 2015),

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276 with a clear organizational structure to interact with the WHO to create a classification system of

277 all manifestations of chronic pain, resulting in 7 categories: musculoskeletal pain, visceral pain,

278 headache, neuropathic pain, post surgical and posttraumatic pain, cancer pain and primary pain.

279 A similar task force should be created to interact with the WHO on the classification of aging.

280

281 Develop an “ideal norm.” Despite the growing abundance of biomarkers of aging, classifying

282 aging as a disease will be challenging due to the absence of the “ideal norm.” Despite significant

283 effort from the academic and industry communities, sarcopenia is still not classified as a disease

284 despite clear clinical and molecular representation and similarity with premature musculoskeletal

285 aging and myotonic disorders (Cruz-Jentoft et al., 2010;Muscaritoli et al., 2010;Fielding et al.,

286 2011;Morley et al., 2011;Mateos-Aierdi et al., 2015). One approach to address this challenge is

287 to assume an “ideal” disease-free physiological state at a certain age, for example, 25 years of

288 age, and develop a set of interventions to keep the patients as close to that state as possible.

289 Considering the WHO definition of health, it may be possible to agree on the optimal set of

290 biomarkers that would be characteristic to the “state of complete physical, mental and social

291 well-being, not merely the absence of infirmity” and agree on the physiological threshold after

292 which the net totality of deviation of these biomarkers from norm can be considered a disease.

293

294 Set effective metrics. When performing cost-effectiveness analysis (CBA), economists often

295 evaluate the outcomes of various programs in terms of the quality-adjusted life years (QALYs)

296 and healthy-years equivalent (HYE) (Mehrez and Gafni, 1989). The most effective altruistic

297 causes are now also evaluated using these metrics (Macaskill, 2015). Studies also demonstrate

298 that each QALY can be valued at $24,777 to $428,286 depending on the method (Hirth et al.,

299 2000). Many projects in aging research do not result in QALY and are currently not prioritized to

300 maximize healthy lifespan (Zhavoronkov, 2013). Classifying aging as a disease would facilitate

301 the development of programs and prioritize projects in aging research that maximize QALY and

302 HYE today and in the future.

303

304 Conclusion

305

306 There are definite benefits for many stakeholders in having aging classified as a disease, and the

307 research community should consider uniting and working as a single voice to increase the chance

308 of having aging classified as a disease by the WHO.

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323

324 Acknowledgements

325 We would like to thank Hantamalala Ralay Ranaivo for reviewing and editing this manuscript.

326

327

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A possibility would be to define two aspects:

1) Detrimental aging process

2) Detrimental accumulated damage

This wording indicates that in order to propose a solution against aging, it should document that the process or the damage is detrimental and it should prove that it does something against it with some clinical benefit.

Edouard, I agree. What do you think about the actual disease codes? 

I think there should be many aging-related codes (inc. sarcopenia), but the R54 should be re-classified. 

There is "Age-related osteoporosis without current pathological fracture" (M81.0) but not the equivalent for sarcopenia. Very strange. The knowledgeable consortium who decides for ICD codes should make a prolonged visit in a nursing home -- no joke here, those are respectable persons -- in order to understand the common and treatable diseases that the ICD-10 roughly hides under R54. It would likely improve health and the productive life expectancy.

In addition to aging processes and damage I would like to make a bold proposition, to help get out of the monopathology aspect of the ICD structure whereas most aged peoples in fact have several serious health conditions:

• The idea comes an observation: science is finding that risk & prevention factors for cardiovascular diseases have a strong overlap with risk & prevention factors for cancers or neurodegenerative diseases. For example, Example of risk factor: smoking. Example of preventing factor: regular physical activity or consumption of fruits or vegetables or some chemical interventions in animal models
• The new ICD item might be called "aging-related risks" (Mxx) and might be defined by sets of age-related diseases (Mxx.0, Mxx.1...), the increasing risk of which is caracteristic of negative aspects of aging. For example, roughly speaking at this stage, Mxx.0 could be increased risk of {cataract, sarcopenia, osteoroporosis, cancer, neurodegenerations, mortality}. If a drug empirically appears to lower all those risks (based on clinical trials or based on large scale retrospective analysis) then it could be used against "aging-related risks".

I recognize that it is a bold proposition but I think it would make sense with respect to the most important needs in health care today. Again, visiting a nursing home helps understand.