The Pathology Of Ageing

Journal of Pathology J Pathol 2007; 211: 111–113 Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/path.2122

Introductory Article

The pathology of ageing: concepts and mechanisms JE Martin* and MT Sheaff Pathology Group, Institute of Cell and Molecular Sciences, St Bartholomew’s and the London Hospital School of Medicine and Dentistry, London, UK

*Correspondence to: JE Martin, Pathology Group, Institute of Cell and Molecular Sciences, St Bartholomew’s and the London Hospital School of Medicine and Dentistry, Pathology and Pharmacy Building, 80 Newark Street, Whitechapel, London E1 1BB, UK. E-mail: [email protected] No conflicts of interest were declared.

Abstract The rising numbers and proportion of aged individuals in the population is a global demographic trend. The diseases associated with ageing are becoming more prevalent, and the associated healthcare costs are having a significant economic impact in all countries. With these changes have come great advances in our understanding of the mechanisms of ageing. The mechanisms of cellular ageing at a genetic, protein and organelle level are becoming clearer, as are some of the more complex associations between environment and ageing. System ageing is also becoming better understood, and the potential biological advantages of ageing are being explored. Many of the advances in these fields are opening up the prospect of targeted therapeutic intervention for ageing and age related disease. Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords:

ageing; pathology; population; mechanisms; therapy

“Age doesn’t matter unless you’re a cheese.”

Putting together some of the current thinking on ageing has been a great experience and challenge. This review issue of the Journal of Pathology addresses both cellular and systems-based aspects of the ageing organism. Ageing — perhaps counter-intuitively — is moving ahead more rapidly than many research areas. New ideas, new ways of thinking about biological processes and new approaches abound [1]. The concept that our inbuilt biodegradability has a useful purpose — to stop us developing tumours — may be of little comfort when considering an imminent knee replacement [2], but scientifically it is actually a whole new area of exploration that has promising therapeutic potential. As we age, we will not be alone. The population demographics of most Western countries are changing rapidly. The proportion of older individuals is rising steadily, due to falling birth rates and declining mortality. Most of us can expect to be around to support and embarrass our children for a lot longer than our grandparents did to our parents. As an example, in the UK, along with an 8% growth in overall population, the proportion of young people has dropped from 25% in 1971 to 19% in 2005; 16% of the UK population are now 65 or older (compared with 13% in 1971), with the percentage of those aged 85 and over rising from 7% in 1971 to 12% in 2005 [3] (Figure 1). Numerically, 1.2 million of the 60.1 million UK population are aged 85 or older. The prediction of UK National Statistics is that ‘population ageing will continue during the first half of this century, since the proportion of the population

aged 65 and over will increase as the large numbers of people born after the Second World War and during the 1960s baby boom become older’. This demographic shift is occurring in many developed nations. In 2004 there were 36.3 million people over 65 in the USA, representing 12.4% of the population. This is expected to grow to 20% of the population by 2030 [4]. The global picture is similar. Key statements from the United Nations overview on ageing [5] include: • One of every 10 persons is now 60 years or older, rising to 1 in 5 by 2050 and 1 in 3 by 2150. • The oldest old (80 years or older) is the fastest growing segment of the older population at 11% of the 60+ age group, rising to 19% by 2050. The

Figure 1. The demographics of the ageing population. Source: National Statistics website [3]. Crown copyright material is reproduced with the permission of the Controller of HMSO

Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk

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number of those aged 100 years or older is expected to increase 15-fold to 2.2 million by 2050. • Striking differences exist between regions. One of five Europeans, but one of 20 Africans, is 60 years or older. • Ageing in developing countries is more rapid than in developed countries and there will be less time to adapt to the consequences of population ageing. • Global life expectancy is currently 66 years; however, in the least developed regions, men reaching age 60 can expect only 14 more years of life and women 16 more, while in the more developed regions, life expectancy at age 60 is 18 years for men and 22 years for women. The global pattern of population change is matched by growth and development in our understanding of the processes involved in ageing. These processes are now being found to operate at systemic levels of the whole organism, and at cellular and genetic levels. The ‘timing’ of cellular ageing, as measured by telomere length, is discussed by Shay and Wright [1]. They highlight the fascinating differences that are currently being discovered between species. As the genetic controls of ageing and associated metabolic processes are becoming clearer, the interaction between cell cycle control and senescence is explored in the article on p53 by Papazoglu and Mills [6]. The central role of autophagy in health and its role in ageing is a hot topic in biology, which is addressed by Terman and colleagues [7]. Ageing-related quality of life depends largely on ageing-related disease, rather than chronological parameters. ‘Natural’ changes in the status of the body with ageing, such as the changes associated with the immune, cardiovascular and endocrine systems [8–14], overlap with ‘disease’ processes, such as those seen in musculoskeletal and skin ‘wear and tear’ [2,9], or cardiovascular disease as described by Greenwald [10]. The interaction and stochastic effects of disease and ageing changes are illustrated in several systems and processes described in the following articles, including ultraviolet exposure and skin damage, noise damage and age-related hearing loss, hypertension and renal function, body mass index and musculoskeletal disease [2,9,10,15,16]. Ageing, it appears, is not just skin deep [9]. Chromosomal, nucleic acid, protein and other macromolecular changes occur at the cellular level with increasing age [7]. It is becoming clear that the pathways involved often have features in common with disease processes, providing insight into some of the mechanisms by which the additive effects of pathology and ‘natural’ ageing occur (Figure 2). In particular, interactions between nutrition, environment, disease and ageing are beginning to be explored, throwing up intriguing ideas about the pathogenesis of major disorders [8,10,11,15,17]. Along with the better understanding of these fundamental processes, there is a glimmer on

JE Martin et al.

Telomeric length

Autophagy

Genetic array Cell age

Systemic factors

Environmental damage

Figure 2. Factors in the ageing process

the horizon of the opportunity to use targeted interventions to modify the ageing process [1,6,8,9]. Better understanding of these processes and the capacity to intervene in them to prevent disease is becoming a healthcare priority. The social and healthcare-associated costs to the individual of declining function with age are readily apparent in the context of both hearing loss and renal function, but with echoes in many of the systems-based articles, including the ageing brain [15–17]. Age-related hearing loss occurs in about 25% of people aged 65–75 and in 70–80% of those over age 75. About 10% of all people over 70 have significant memory problems and about half of these are due to Alzheimer’s disease (AD). The number of people with AD doubles each decade past age 70. With the rise in the very elderly population, the disease burden and its impact is considerable, not just for patients but also for carers. The costs of particular age-related diseases have been well quantified. Maintaining a patient with endstage renal failure on renal replacement therapy currently costs approximately £20 000/patient/year for a patient on peritoneal dialysis and £22 000/patient/year for a patient on hospital haemodialysis [18]. The cost of ageing-associated diseases is likely to expand dramatically. Jean-Phillipe Codis, in an address to the European Federation of Pharmaceutical Industries and Associations in Athens, 2003, stated that the percentage of gross domestic product (GDP) spent on healthcare is expected to rise from 6% to 9% due to ageing alone. Whilst there is little biological or economic cause for complacency in this area, there is a great deal of exciting research and discovery in the field and this review issue brings together many of the key findings and advances that are promising to bring some spring back into autumn.

J Pathol 2007; 211: 111–113 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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References 1. Shay JW, Wright WE. Hallmarks of telomeres in ageing research. J Pathol 2007;211:114–123. 2. Freemont AJ, Hoyland JA. Morphology, mechanisms and pathology of musculoskeletal ageing. J Pathol 2007;211:252–259. 3. National Statistics website: www.statistics.gov.uk. 4. Administration on Aging website: www.aoa.gov. 5. Population Division, Department of Economic and Social Affairs, United Nations Secretariat, New York, USA. 6. Papazoglu C, Mills AA. p53: at the crossroad between cancer and ageing. J Pathol 2007;211:124–133. 7. Terman A, Gustafsson B, Brunk UT. Autophagy, organelles and ageing. J Pathol 2007;211:134–143. 8. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 2007;211:144–156. 9. Baumann L. Skin ageing and its treatment. J Pathol 2007;211:241–251.

10. Greenwald SE. Ageing of the conduit arteries. J Pathol 2007;211:157–172. 11. Chahal HS, Drake WM. The endocrine system and ageing. J Pathol 2007;211:173–180. 12. Sampson N, Untergasser G, Plas E, Berger P. The ageing male reproductive tract. J Pathol 2007;211:206–218. 13. Djahanbakhch O, Ezzati M, Zosmer A. Reproductive ageing in women. J Pathol 2007;211:219–231. 14. Walker RA, Martin CV. The aged breast. J Pathol 2007;211:232–240. 15. Liu XZ, Yan D. Ageing and hearing loss. J Pathol 2007;211:188–197. 16. Martin JE, Sheaff MT. Renal ageing. J Pathol 2007;211:198–205. 17. Esiri MM. Ageing and the brain. J Pathol 2007;211:181–187. 18. www.uktransplant.org.

J Pathol 2007; 211: 111–113 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.