The New Science of Ageing APRIL 2015 CHAPTER TWO : UNDERSTANDING AGEING

Ageing This chapter begins by explaining that ageing is “Multi-dimensional”, defined by: ▪ Biological Reality of Ageing - loss of function and increased mortality with age. (Typical examples: reduced mobility, reduced lung capacity, slower response times, impaired sight and loss of hearing)

▪ Social and Cultural Context – loss of status, reduced social activities and interactions. Social constructs eg definitions of child/adult ▪ Psycho-social Factors – health policies, pensions and social attitudes can affect older peoples’ feelings of value/worth

Biological Ageing Usually defined as a progressive loss of function, accompanied by decreasing fertility and increasing mortality with advancing age…. Thomas Kirkwood (Department of Gerontology, University of Newcastle) suggests ageing cannot be explained simply as the inevitable result of biological wear-and-tear Approx. 200 mechanisms of biological ageing have already been identified.

……..Chapter raises the question, why has ageing evolved?

Evolutionary theories of Ageing Theories summarised by Kirkwood and Austad (Nature, Vol 408, 9 Nov 2000) include:

1. Genetic Programming – Ageing/senescence is pre-programmed in order to limit

population size, accelerate the turnover of generations and hence help organisms to adapt to changing environments… BUT senescence does not contribute significantly to mortality in the wild.

2. Pleiotropy – This theory proposes that Pleiotropic Genes (those that bring benefit in early life) would be favoured by selection even if they had deleterious effects in later life

3. Life-History Trade-off – Based on the optimal allocation of resources ie trade-off

between resources required for reproduction and those required for somatic (body) maintenance into old age. Investment in reproduction over longevity

“Hayflick Limit” ▪ The phenomenon of cellular aging was first noted by Lenhard Hayflick in 1961. ▪ Hayflick discovered that cells cannot divide beyond a specific number of times. This is called the Hayflick Limit.

▪ Cells reaching this limit become old.

Hayflick Limit and Telomeres ▪ In 1990, Calvin Harley (Canada) and Carol Greider (USA) discovered that shortening of telomeres (tips of chromosomes) is associated with the aging process and the direct cause of cells reaching the Hayflick Limit.

▪ People over 60 with long telomeres experience greater heart and immune system health than those of same age with shorter telomeres. ▪ See diagram on next slide…..

Role of Telomeres in Cell Reproduction and Ageing ▪ Telomeres are the caps at the end of each strand of DNA that protect our chromosomes (similar to the plastic tips at the end of shoelaces). ▪ Telomeres are an essential part of human cells; they are involved in cell reproduction and are implicated in cell ageing.

Telomeres in cell reproduction

Senescent Cells ▪ Some rapidly dividing cells reach a point when they can no longer reliably replicate; their telomeres become too short to protect the cell’s DNA. At this point, a cell will either : ▪ destroy itself through a process called apoptosis, ▪ become dysfunctional (and potentially cancer-prone), or ▪ turn replication off but continues to survive. ▪ Cells that turn off are known as senescent. They can perform some functions, but they also release molecules that may increase risk of disease ▪ The gradual build up of senescent cells over a human life time is believed to underlie many of the conditions (pathologies) associated with old age.

Ageing at cell, tissue and organ level - Some cells (eg lining the gut, skin, blood, mucous membranes) are regularly lost. - These need to be replaced. - These cells are especially susceptible to senescence.

Molecules and Cells

Flaws at molecular/ cellular level

Collection of Cells = Tissue Tissues

Collection of Tissues = Organ

Decline and Failure

Organs/System

Organ/System

Death

Cell Senescence ▪ Cell Senescence is thought to be an important anti-cancer mechanism – it prevents old cells (with accumulated damage to their DNA) from proliferating. ▪ This is demonstrated by the finding that many cancers develop as a result of a faulty gene that affects the expression of an enzyme “telomerase”

▪ Essentially, this enzyme adds telomere ends to chromosomes and resets the “Hayflick counter” to zero (cells become immortal.

Tissue and System Ageing A Tissue is a collection of cells that make a structural whole and perform a specific function in the body.

Tissues deteriorate with age. Examples used in this chapter include:: ▪ muscle wastage

▪ skin elasticity ▪ wound healing. Organs (eg heart) are made up of different tissues.

Tissue and System Ageing A System is a coherent collection of different types of cells/tissues/ organs that all work together as a unit. There are 10 major systems in the body, each of which plays a different role in helping the body to function. Examples given in this chapter:

▪ Cardiovascular system (heart and lung functions deteriorate with age) ▪ Nervous system (motor skills, eyesight, hearing, reflex responses )

▪ Immune system (immune system is compromised with age)

Studying Health and Vigour into Old Age Some groups of individuals retain high levels of health and vigour right up until death. A large proportion of them live to be centenarians. Such groups include:

▪Okinawa Japanese ▪Ashkenazi Jews in New York

Okinawa Japanese ▪ Japanese are the longest-lived ethnic group globally (National Geographic 1993). ▪ Okinawa Japanese reported to live longer on this island than anywhere else in the world. ▪ Five times as many Okinawans lived to be 100 as in the rest of Japan. ▪ JWA Santrock (2002) cited there were 34.7 centenarians for every 100,000 inhabitants ie the highest ratio worldwide.

Okinawa Japanese Some possible explanations for their longevity are: ▪ Diet (fish, tofu, low-fat)

▪ Low-stress lifestyle ▪ Caring community

▪ Physical activity ▪ Spirituality of the inhabitants of the island.

Ashkenazi Jews

▪ Show a marked reduction in age-related disease compared with general population ▪ Live active, healthy lives to extreme old age (often 11th decade) ▪ During much of their history the Askenazi Jews experienced significant reductions in their population. ▪ Today, they number approximately 8 million

Ashkenazi Jews ▪ Ashkenazi Jews are descendants from a small number of “founders”. One study suggests that 40% of today’s population come from just four “founding mothers”.

▪ It follows that the genetic makeup of Ashkenazi Jews is relatively homogeneous. This makes it easier to identify the location of genetic variations. ▪ Gene mutations responsible for early onset ovarian cancers and breast cancer were identified from research with Ashkenazi.

National Institute on Aging (US) The Institute's mission is to: ▪ Support and conduct genetic, biological, clinical, behavioural, social, and economic research on aging.

▪ Foster the development of research and clinician scientists in aging. ▪ Provide research resources.

▪ Disseminate information about aging and advances in research to the public, health care professionals, and the scientific community. ▪ Good source of information on research highlights and findings.

Studies of Super Centenarians Genetic analysis of these super-centenarians show a handful of genes that predispose the individuals to healthy old age Baltimore Longitudinal Study of Ageing (BLSA 1958 – present) ▪ Showed wide variation across populations

▪ Concluded that individual genes make only a tiny contribution to ageing. Rather, ageing is polygenic, i.e. determined by multiple genes acting together ▪ www.nia.nih.gov/newsroom/research-highlights

Gene Variants - Super Centenarians ▪ A gene is sequence of DNA. It occupies a specific position on a chromosome, and determines specific characteristics/traits ▪ Some gene mutations result in premature ageing eg Werner Syndrome ▪ Some gene variants in super centenarians are important in regulating cholesterol in blood (HDL) ▪ Other gene variants impact blood pressure, DNA repair and electrical insulation of the brain

Cholesterol (HDL and LDL) ▪ Low-density lipoproteins (LDLs) carry cholesterol to the tissues. Often referred to as "bad" cholesterol because high LDL levels linked to increased risk of heart disease ▪ High-density lipoproteins (HDLs) carry excess cholesterol back to liver, which processes and excretes it. Often termed "good" cholesterol; the more HDL you have, the lower the risk of developing heart disease.

▪ HDLs and LDLs are found only in your blood, not in food.

Some other observations…. Environmental conditions may affect gene expression:

▪ Stress and higher levels of stress hormones (cortisols) are associated with shortening of the telomeres –a key driver of ageing ▪ Diet/Nutrients ▪ High levels of nutrients stimulate cell proliferation (see page 40 mTORC1). ▪ Calorie restriction (or agents that inhibit mTORC1) results in cell autophagy (clean up cellular debris) and increased cell longevity. (see page 41 - study of worms, 1998 and page 65 - rats)

Changing/Improving Ageing Chapter closes with focus on ways of modulating ageing in humans:

(1) Calorie restriction (CR) ▪ Limited research shows weight reduces, so too does BP and cholesterol, but extreme CR can lead to lethargy, depression and, perhaps, reduced immunity. ▪ CR may increase health span but changes in life span is more difficult to ascertain due to the effect of other factors eg medical interventions, public health.

Changing/Improving Ageing (2) Drug interventions ▪ Rapamycin – inhibits TORC, regulates insulin pathway. Found to extend lifespan in yeast and mice. ▪ May equate to 10 years in human females (Harrison et al 2009). ▪ Also, Spilman et al (2010) has shown health benefits, notably Alzheimer’s ▪ Rapamycin is currently licensed for use in clinic with transplant patients as an immune suppressant. Likely to be used in clinical trials for progeria treatment soon. ▪ Other agents eg metformin (an anti-diabetic) is also promising.

Changing/Improving Ageing (3) Telomerase – enzyme repairs ends of chromosomes. ▪ Studies on mice with signs of ageing showed rejuvenation when this enzyme was reactivated (Jaskelioff et al 2011). ▪ Could be used as a means of regeneration. ▪ But other studies have indicated that telomerase reactivation promotes aggressive tumour formation (Ding et al 2012)

Changing/Improving Ageing (4) Gene Modification Manipulation of genes that affect the manufacture of proteins (eg progerin) which influence ageing. (5) Immune System and Hormonal Modification – Supplements and therapies to restore function

Ethical Questions ▪ Max life span remains at approx. 120 yrs but with recent advances in BIOGERONTOLOGY this could be extended ▪ Societies combat disease to extend life, why not combat ageing to extend life too? ▪ Will structure and dynamics of society be altered ? Will this be positive or detrimental? ▪ Life span v. health span? Mortality v. Morbidity? Active ageing v Immortality? ▪ Economics – impact on health and social care costs? ▪ Alter the dependency ratio ie producers v consumers?