Biology of Aging

Siri Rostoft, MD, PhD

Department of Geriatric Medicine

Oslo University Hospital

Norway

Disclosure

No conflicts of interest to declare

Patient, 96 years

“ ……you know, I am not

80 years anymore…….”

Who is older?

• 10 years older than the treating physician

• Literature: varies from 65-75 years

DISPOSITION

• Life expectancy increases

• Longevity

• What happens to the body when we age?

• Heterogeneity – fit versus frail

• Aging biomarkers

Life expectancy increases

•UK: Life expectancy increases

at the rate of 5 hours per day¹

• Why declining late-life

mortality?

¹Kirkwood Nature 2008

100 Years Old. 5 World Records.

The New York Times, September, 2015

QUIZ

• What is the percentage of people aged 80 years who are independent in their daily life?

• 20%

• 45%

• 75%

What about functional status?

• The majority of people who are 80 years have

a good functional status and live independent

lives (75% in Swedish study) even if they have

chronic diseases

• Often large changes in health and function

between 80-85 years

Santoni et al Plos One 2015

Death rate in older people

• Most babies born since 2000 in France, Germany,

Italy will celebrate their 100th birthdays

• Extreme longevity = extreme disability?

• The answer is still open

• Difference between population level and

individual level

Christensen et al, PNAS 2008

Danish study

• Proportion being independent around 0.4 in

all ages, 92 to 100

• High rate of mortality among the most

disabled at any time

• 90 – only halfway to 100 (0-92 1:30, 92-100

1:30)

Christensen et al, PNAS 2008

Getting better (population level)

• 1915 cohort performed better than did the

1905 cohort in cognitive functioning and ADL

• No differences in performance measures

• ADL better due to better cognitive functioning

and better living conditions

Christensen Lancet 2013

Declining prevalence of dementia

• A reduction of 24% of dementia in two

cohorts in England and Wales1

• Participants in the Framingham Heart Study

– incidence of dementia has declined over the

course of three decades 1980s ref to 2010

– 22%, 38%, and 44%2

1Matthews et al, Lancet, 20132Satizabal_NEJM_2016

Quiz

• What is the most common cause of mortality

in people under the age of 85?

• What about people over the age of 85?

• Alternatives

– Cancer

– Heart disease

– Infectious disease

Causes of mortality (US)Death rates of cancer and heart disease for ages younger

than 85 and 85 and older

What is aging?

• Defined as

– Progressive loss of function

– Reduced fertility

– Increased risk of mortality

• Deteriorative process

1. Increases probability of dying

2. Decreases ability to withstand extrinsic stresses

Kirkwood Nature 2000

Natural selection and aging

• Species that have a long lifre span live in a

protected environment (humas)

• Age-related diseases often occur after

reproductive age – the genes are not removed

• Aging leads to accumulated damage – good

genes for repair and maintenance lead to

better aging

Aging

• Happens due to biological processes

• Biological processes lead to changes in

physiological variables

• The calendar cannot be used to measure aging

Arking: Biology of aging, 3rd ed

PHYSIOLOGY OF AGING

Aging - levels

• DNA

• Other molecules, cells

• Free radicals (important to kill bacteria,

negative for aging)

• Tissues and organs

• Organ systems

• System level

“After age 30, it is all downhill”RA Marottoli, 2011

Physiology of aging

1) Mortality increases with increasing age

2) Body composition changes with increasing age

(muscle is replaced by fat)

3) Decline in capacity with increasing age (maximum

pulse↓, kidney funcNon↓)

4) Reduced capacity to deal with stress (surgery,

infection), difficult to sustain homeostasis

5) Increased risk of disease and increased vulnerability

when getting sick (i.e. pneumonia)

Reduced ability to deal with stress

Lakatta Aging 1994

Decrease in capacity - heterogeneity

Muravchik, Anesthesia 5th ed, 2000

25

Forventet gjenstående levetid

Walter LC, JAMA 2001

Remaining life expectancy

Healthy aging

• The ultimative preventative medicine

• Age is the greatest risk factor for nearly every

major cause of mortality

• Biomedical research focuses on individual

disease processes

• Should focus on molecular processes that

underlie biological aging – particularly on

interventions that delay aging

Kaeberlein et al, Science 2015

• Multimorbidity

• Polypharmacy

• Functional disability (need assistance in everyday life)

• Cognitive impairment or dementia

• Malnutrition

• Lack of social network

• Evidence-base is non-existing

GETTING OLDER….

BIOMARKERS OF AGING

Why do we need biomarkers?

• Calendar is insufficient to measure aging in

individuals

• Are there biomarkers that could help us?

Ideal biomarkers

• The rate of change with time in a biomarker

should reflect the rate of aging

• The biomarker should be monitoring a basic

and important process

• Nonlethal and preferably noninvasive test

• Highly reproducible results

• Functions being measured should be curcial to

maintain health

Arking, The biology of aging, 3rd ed

• Biomarker should be able to funbction as a

prospective predictor of life span

• 1) Predict outcome of a broad range of

physiological domains, better than

chronological age

• 2) Predict remaining longevity

Examples

• Grip strength – predicts premature mortality

in men >60 years

• FVC (forced vital capacity)

• White blood cell count

• Cholesterol (age specific)

• BMI (age specific)

Visual estimates

1. Older looking twin dies first Christensen et al. BMJ 2009

2. Residents’ illness severity ratings were the most

significant predictor of in-hospital mortalityCharlson et al. J Chron Dis, 1986

3. Individuals who looked older were biologically

olderBorkman Soc Sci Med.1982

Biomarkers of frailty

• One may look at aging as a pro-inflammatory

state

• “Inflammaging”

• Increased sectretio of pro-inflammatory

cytokines

• Examples: CRP, IL-6, TNF-α associated with a

higher risk of all-cause mortality

• Frail individuals have higher levels

Other biomarkers

• D-dimer (aging associated with activation of coagulation?)

• Telomere length – decreased length=associated with mortality and disability

• Glascow prognostic score (measure of systemic inflammation based on CRP and albumin)

www.pnas.org/cgi/doi/10.1073/pnas.1506264112

Used biomarkers from people aged 26-38 to calculate pace of aging. Based on clinical

examinations, examples were BMI and cardiorespiratory fitness

DNA methylation age – epigenetic

clock• Epigenetic signatures show a strikingly accurate way to

measure human aging

• Modifications to the genome that does not alter the DNA sequences but can influence how genes are expressed

• The method allows for estimation of DNA methylation age of most tissues and cell types

• DNA methylation age measures the cumulative effect of an epigenetic maintenance system

Horvath S Geome Biol 14 (2013)