Physiology of Ageing

Dr Tessa La Varis Consultant General Physician & Geriatrician 11 March 2011

Principles of Ageing Theories of Ageing Ageing of Specific Systems

External appearance Brain/Neurology

Heart/Lungs
Endocrine/Metabolic Musculoskeletal Genitourinary

Successful Agers Frailty Anti-Ageing Phenomenon

Principles of Ageing
Age and age related diseases are not the same Those manifestations that are universally present in all elderly and increase in magnitude with advancing age represent ageing

There are a range of individual responses to ageing

Body systems do not age at the same rate Even changes that are considered normal do not result in inevitable consequences First detectable as a loss of reserve capacity

Principles of Ageing
Normal ageing in the absence of disease is quite benign. Although organs gradually lose function, changes are not always noticed until times of great exertion and stress.

Principles of Ageing

Theories of Ageing
The Evolutionary Theory
Defines ageing in terms of natural selection and its relationship with fertility The Grandmother Effect

Mutation accumulation theory

Ageing is an inevitable result of the declining force of natural selection Mutant genes that kill young will be strongly selected against Lethal mutation that kills the old will experience no selection and over generations will accumulate
Genes beneficial at younger age become deleterious at older ages

Antagonistic Pleiotrophy

Theories of Ageing
Telomerase Theory of Aging
Normal cells lose the ability to divide after ~50x in vitro (cellular senescence). Related to telomere length. Shorten with each division.

Each time a cell divides, it duplicates itself a little worse eventually leading to cellular dysfunction and death
This is protective against malignancy Does not occur in all organisms or cell lines (cellular immortality)

The Rate of Living Theory/Free Radical Theory

Free radicals (by-product of normal metabolism) Damage cells Theory: metabolismlongevity Theory proven in Roundworm &

Fruit-fly but not Mice

Ageing on the Outside

Ageing on the Outside

Skin
Oil glands and underlying fat thinner/drier/wrinkly Atrophy of sweat glands heat tolerance Age Spots Solar Lentigo Deposits of melanin in skin (sun exposure)

Nails

thicken due to blood supply growth 50%

Hair

thins and loses pigment

Ageing Brain
Weight and volume of brain by 2%/decade from early adulthood

Neurotransmitters
Serotonin Acetylcholine Dopamine

Number of inter-neuronal connections in some parts of the brain Personality and Sense of Self is unchanged

Neuron density
30% by age 80

Ageing Cognitive Function

Frontal lobe is most negatively affected by normal ageing
Speed of processing and learning new information Working memory (retention of information that must be manipulated) Difficulty with word retrieval Difficulty distinguishing relevant and irrelevant information to a task resulting in impaired attention. Changes to executive function

Positive Changes

Greater experienced based knowledge Increased accuracy Better judgement Better ability to handle familiar tasks

Ageing Cognition
Changes happen to everyone to a degree with wide variation.

Memory problems that are not part of normal ageing:

Forgetting things much more often than you used to Forgetting how to do things youve done many times before Trouble learning new things Repeating phrases or stories in the same conversation Trouble making choices or handling money Not being able to keep track of what happens each day

In many the changes are undetectable and should not interfere with normal day to day functioning

By the age of 80 only 30-40% of people have a significant decline in mental ability

Ageing Co-ordination
Proprioception Cerebellar and Vestibular cells

Balance
Delay in speed of nerve conduction

Reaction time and Sensation

Ageing Senses - Vision

Pupils less responsive
Tolerance to glare Need for illumination Light/dark adaptation

Retinal Changes
Colour perception Contrast sensitivity

Hardening of lenses
Depth perception Accommodation

Ageing Senses Hearing & Taste

Hearing
50% >85yrs experience significant hearing loss Eardrums thicken, auditory canal walls thin High frequency hearing

Taste
Number of taste buds Sense of thirst

Ageing Sleep
Melatonin secretion is lower Slow wave/delta sleep

Latency to sleep onset

Awakenings Tendency for sleeping and sleepiness during the day

Maturity is a Distinct Phenomenon from Ageing

Ageing Heart
Increasing arterial rigidity Heart muscle efficiency

diastolic dysfunction

Impaired baroreceptor response

postural hypotension

Response to adrenergic stimulation

maximum attainable stroke volume / ejection fraction / cardiac output oxygen delivery

Complicated by presence of disease

Ageing Lungs
Structural support for small airways
number of small airways open susceptibility to infection

CNS responsiveness Muscle mass including muscles of respiration Elasticity

Vital capacity loss of 5-20% of functional ability/decade Residual volume

PaO2

Age 20 952 Age 75 73mmHg 5

Ageing Endocrine Hormones

Hypothalamic Pituitary Function
Circadian rhythm shifts Reduced GH Lean body mass and bone density

DHEA Dehydroepiandrosterone
Precursor to Estrogen and Androgen Concentration 80% between age 2080 No clear consequence

Adrenocortical Function
Sustained cortisol levels

?Effect

Ageing Eating
Factors causing weight loss with age

Ageing Metabolism
1% metabolic rate/year >25
Proportion of body fat doubles age 2575
Can be influenced by exercise

Susceptibility to drug toxicity

Weight
Men until 50s then Women until 60s then slow

Glucose regulation
insulin sensitivity (50%) insulin production (Variable)

Obesity, Muscles and Exercise

As we age, fat increases and muscle and bone decrease, worsened by chronic inflammation and inactivity =sarcopenic obesity Skeletal muscle mass decreases 3kg/decade from age 45yrs; strength reduces 1-2%/yr from 40yrs Resistance training increases muscle mass and strength, decreases fatty infiltration of muscle, mobilises visceral fat, decreases insulin resistance, improves gait, balance and function Adding aerobic exercise further reduces diabetes and CVD risk, but requires muscle to start with! Visceral adiposity increases with age and is high risk, so consider measuring waist-hip ratio

Relative Risk of Death Associated with Obesity Decreases with Age

Avoiding Weight Loss

Anker 1997: Wt loss >7.5% = RR 3.73 mortality
Fiedal 2005: BMI <18.5 in >60 year olds increases mortality 4.8% malnourished and 38.4% at risk of it in domiciliary care in Adelaide 2003 Starvation: low caloric intake causes low LBM and fat mass, this CAN be reversed with feeding Sarcopenia: low LBM, stable weight (measure midarm circumference to detect) Cachexia: chronic inflammatory disease, cytokine mediated, CAN NOT be reversed with feeding

But It Happens Anyway

Ageing Musculoskeletal
Bones
Maximum mass Age 25-35 Vertebral thinning Height Vertebral calcification Rigidity

Joints
Weight bearing joint space

Height until age 40 then up to 5cm by age 80

Proprioception

Ageing Vitamin D & Calcium

Vitamin D
Important for bone and muscle strength With age, generation from sun exposure Conversion 25 - 1,25 hydroxy vitamin D Resistance to Vitamin D action

Calcium absorption is decreased

Osteoporosis
Estrogens (and testosterone to lesser extent) combine with the above to lead to reduced bone mineral density

Ageing Menopause
Abrupt change Estrogens & Androgens =Menopause
Menstrual irregularity
Uterine wall changes

Vasomotor Hot Flushes

Hypothalamus thermoregulation dysfunction

Vaginal and Urethral changes Sleep disturbances

Ageing Male Hormones

Testosterone (1%/year) from 20s Sperm production stable 70 then 50% by age 90
Variable consequences

Andropause?
Sexual function Bone density muscle mass/strength Cognitive function

Trials of testosterone replacement

BMD if levels very low Muscle mass but not strength No change in QOL and sexual function Potential increase in disease

Ageing Genitourinary
Bladder sphincter muscles lose strength Vagina Lubricates more slowly and with less amount
Shortens and narrows

Prostate enlarges
Kidneys lose 20% mass age 40-80
GFR 1ml/min/yr >40 (normal 80-120) (Serum creatinine poor measure) ability to dilute and concentrate urine

Successful Ageing is Happening

Successful Agers
Marion Griffiths
Age 71 2007 ran a marathon for every decade of her life

Okinawan Japanese have:

more people over 100 years old per 100,000 population than anywhere else in the world the lowest death rates from cancer, heart disease and stroke (the top three killers in the US) the highest life expectancy for both males and females over 65 females in Okinawa have the highest life expectancy in all age groups

Centenarians are 85% Women, Thin and Doubling in Number Every Decade Besse Berry Cooper
Born August 26 1896 Alive in Monroe, Georgia, USA

Jeanne Louise Calment

21 February 1875 4 August 1997 122 years, 164 days

Frailty Defined, Not Inevitable

A physiologic syndrome characterized by decreased reserve and resistance to stressors, resulting from cumulative decline across multiple physiologic systems, and causing vulnerability to adverse outcomes.

Fried et al. 2003

Features & Predictors of Frailty

Weight loss 5% body weight in last year Exhaustion Weakness Slow walking speed > 6secs to walk 5m Decreased physical activity Extreme age Visual loss Impaired cognition/mood

Limb weakness
Abnormalities of gait and balance

Sedative use
Multiple chronic diseases

How the Frail Present with Illness

Classical
Silent/Pseudo-silent Atypical Presentations
Weakness/Fatigue Falls/Immobility Cognitive/Mood Change Dwindles Incontinence Social Crisis

Anti-Ageing Phenomenon
Human Growth Hormone DHEA Coenzyme Q Lipoic Acid Green tea extract Fish oil Folic acid Testosterone, Estrogens and Progesterone Extreme Caloric restriction Vitamin and amino acid concoctions to make you look and feel younger and taller

Anti-Ageing Phenomenon
Growth Hormone
Trials in healthy older people body fat & muscle mass no change in strength (and SEs ++)

Exercise body fat & muscle

mass & strength

DHEA Dehydroepiandrosterone
Higher levels associated with longevity in primates and humans Trials of replacement in rats worked, but not in humans

Caloric Restriction
Shown to prolong life in mice, worms,fish,flies,yeast No evidence that people live longer

Resveratrol

Old age isnt so bad when you consider the alternative

The Perks to Being >50yrs

No one expects you to run into a burning building. In a hostage situation you are likely to be released first. You enjoy hearing about other people's operations. People no longer view you as a hypochondriac.

You no longer think of speed limits as a challenge.

Your investment in health insurance is finally beginning to pay off. You sing along with elevator music. You quit trying to hold your stomach in, no matter who walks into the room.

Your eyes won't get much worse.

Your joints are more accurate meteorologists than the national weather service. You have a party and the neighbours don't even realise it. Your supply of brain cells is finally down to manageable size.

Watkins The American Journal of Clinical Nutrition 36: OCTOBER 1982, pp 750-758.
The health status of older persons is directly related to the lifestyles they have practiced or which were imposed on them during infancy, childhood, adolescence and adulthood, as well as the presence of chronic diseases Belloc and Breslow 1972 (39) clearly demonstrated the desirable effect of lifelong devotion to seven good health practices. These are, slightly paraphrased:
avoid gluttony, tobacco, and excessive alcohol consumption; eat nutritionally adequate and regularly scheduled meals; incorporate into ones lifestyle regularly scheduled hours of sleep, exercise, and rest and relaxation MUM WAS RIGHT!

Watkins The American Journal of Clinical

Nutrition 36: OCTOBER 1982, pp 750-758.
The most obvious change associated with physiological aging in mature adults is that of personal appearance. The graying hair, the wrinkling skin, the changes in bodily external dimensions, and the almost inevitable resort to prostheses such as eye glasses and hearing the gradual diminution of carbohydrate tolerance, the almost linear decrements in discrete renal functions, the fall in cardiac index, the diminution in maximum breathing capacity, the decline of nerve conduction velocity, the reduction in ability to taste and smell, the fall in isoimmunity titers and the rise in autoimmunity titers, and the decrements in muscle strength, to mention only a few parameters. Many effects deleterious to performance coincide temporally with aging but are in fact created by the superimposition on physiological aging of disease processes.

Watkins The American Journal of Clinical Nutrition 36: OCTOBER 1982, pp 750-758.
Fasting blood glucose and blood pH change little; nerve conduction velocity and cellular enzyme activities drop about 15% in a lifetime; cardiac index falls 30%; and vital capacity and renal blood flow fall by 50%. However, maximum breathing capacity, maximum work rate, and maximum 02 uptake fall by 60 to 70%. The last mentioned performances require integrated activity of the cardiovascular, nervous, muscular, and respiratory systems and show the greatest decrements with age The variation within a particular age cohort is often nearly as great as the variation among age cohorts. This leads to the conclusion that in cross-sectional studies, no single age emerges as the point of sharp decline in function. This observation is particularly important in making decisions in regard to whether a specific person should be forced to retire Basal metabolic rate (BMR) falls on the average about 20% between ages 30 and 90 as measured in cross-sectional studies (27). Since no differences in the ability of the thyroid gland to produce or release thyroxine have been demonstrated (28), other explanations are required. Fat and connective tissue proportions of the body are known to increase as total body water decreases with age, though the water content of oxygenconsuming cells does not change significantly. The fall in basal metabolism with age is a reflection of the loss of metabolizing tissue with age. Loss of lean body mass, reflected by the dramatic decrease in body water, is a basic fact of the aging process in man. The tissue loss is caused by cell death that in turn has numerous causes.

Watkins The American Journal of Clinical Nutrition 36: OCTOBER 1982, pp 750-758.
Energy intake decreases with advancing age. Studies conducted at the Gerontology Research Center in Baltimore by McGandy et al (32), have shown conclusively that men from age 28 onward tend to consume less energy. Simultaneously, they have small annual reductions in basal energy expenditures. The greatest annual reductions are in voluntary activities. Hence, the total heat that must be eliminated in the old is substantially less than that in the young. There is substantial evidence to indicate that the response to low or to high environmental temperatures is less effective in the old than in the young. As far as cold is concerned, the evidence suggests that older persons can increase their heat production as well as the young but that their mechanisms involved in heat conservation are not as effective (33). As far as heat tolerance is concerned, epidemiological studies of heat stroke indicate that the death rate rises sharply after age 60 (34). The mortality rate rises with both increasing temperature and with advancing age, suggesting that decrements with age occur in heat dissipating mechanisms (35). These few examples show not only changes in individual organ or metabolic systems but also support the concept that aging of the total human being is more than the summation of changes occuring at the cellular, tissue, organ, or single-system level. Human life requires the integrated activity of all organs and systems to cope with the stresses of living. With advancing age, the regulatory mechanisms are less effective. Hence, as persons age, their ability to adapt is diminished (36).

References Donald M Watkin The physiology of aging

27. Shock NW, Yiengst Mi. Age changes in basal res- piratory measurements and metabolism in males. J. Gerontol 1955; 10:31-40. 28. Baker SP, Gaffney GW, Shock NW, Landowne M. Physiological responses of five middle-aged and el- derly men to repeated administration of thyroid stimulating hormone (thyrotropin; TSH). i Gerontol 1959; 14:37-47. 32. McGsndy RB, Barrows CH ir, Spanias A, Meredith A, Stone JL, Norris AH. Nutrient intake and energy expenditure in men of different ages. J Gerontol 1966;2 1:581-87 33. Krag CL, Kountz, WB. Stability of body function in the aged. I. Effect of exposure of the body to cold. i Gerontol 1950;5:227-35. 34. Driscoll DM. The relationship between weather and mortality in the major metropolitan areas in the 758 WATKIN United States, 1962-1965. lnt J Biometeorol 1971; 15:23-39. 35. Oechsli FW, Bueckley RW. Excess mortality asso- ciated with three Los Angeles September hot spells. Environ Res 1970;3:277-84. 36. Shock NW. Systems integration. In Finch CE, Hay- flick L, Brody H, Rossman I, Sinex FM, eds. Hand- book of the biology of aging. New York: Van Nos- trand Reinhold Co, 1977:639-65. 39. Belloc NB, Breslow L. Relationship of physical health status and health practices. Prey Med 1972; 1:409-2 1.

Physiology of ageing Review Article Anaesthesia & Intensive Care Medicine, Volume 11, Issue 7, July 2010, Pages 290-292 Simon L. Maguire and Benjamin M.J. Slater
Abstract: The impact that ageing has on organisms is a complex interaction between the processes of ageing at a cellular, organ and integrated systems level, and the effects of environmental factors such as nutrition, infection and trauma. Recovery from an insult that triggers a pathological response is never complete. The incremental fall in possible performance is part of the progressive diversity in physiology that is the true hallmark of ageing. In this article we will outline some of the physiological changes, particularly cardiorespiratory, associated with the ageing process that will be of relevance to anaesthesia.

Theories of ageing, Respiratory system, Cardiovascular system, Exercise, Energy and temperature regulation, Summary, References