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 stressors

Kirkwood Nature 2000

Aging

• Explained by biological processes

• Biological processes lead to changes in

physiological variables

• The calendar cannot be used alone to

measure aging

Arking: Biology of aging, 3rd ed

There is no gold standard tool for assessing healthy

ageing at the individual or population levels.

Shamir L. et al - Gerontology 2015

Ferrucci L. - PLoS ONE 2015

Main issue

From Marije Hamaker

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

System Age-related changes Effect of anesthesia Clinical effect

Cardiovascular (including

autonomic nervous system)

Hjertet og blodkar stivere

VV hypertrofi

Redusert respons på katekolaminer

Redusert baroreseptorrespons

Redusert antall pacemakerceller

Dilatasjon av blodkar

Redusert kontraktilitet

Redusert baroreseptorrespons

Større fluktuasjoner i preload ved volumendring

Risiko for væskeoverload, avh av å øke endediast

volum

Svekket takykardirespons

Økt risiko for hypotensjon

Økt risiko for arytmi

Lung/respiratory Tap av elastisitet

Muskelatrofi

Brystveggen stivere

Svekket gassutveksling

Redusert respons på

hypoksi/hyperkapni

Hosterefleks svekket

Dysfagi, redusert øsofagusmotilitet

Redusert tidevolum, FRC

Hemning av hypoksisk vasokonstr,

V/Q mismatch

Redusert respons på

hypoksi/hyperkapni

Hosterefleks svekket

Ciliene mindre effektive

Økt pustearbeid, økt dødvolum

Tap av kapasitet

Redusert gassutveksling, risiko for hypoksemi og

hyperkapni

Økt risiko for stagansjon av sekret og

aspirasjonspneumoni

Immune system Thymus tilbakedannes

Færre B-celler og naive T-celler

Økt lavgradig inflammasjon

Immunsuppresjon (kirurgi) Økt risiko for sepsis

Økt risiko for akutte virale infeksjoner

Dårligere respons på vaksinering

Økt morbiditet og mortalitet

Nervous system Reduksjon i nevronstørrelse og

forbindelser

Inhibisjon av

nevrotransmitterfunksjon

Kognitiv svikt/sårbarhet

Økt risiko for delirium og POCD

Kidneys Redusert blodstrøm og GFR

Redusert tubulær funksjon

Redusert blodstrøm og GFR Redusert eliminasjon av medikamenter

Risiko for akutt nyresvikt

Salt/vann homeostase vanskeligere å regulere

Endocrine system Redusert glukosetoleranse Redusert glukosetoleranse Hyperglykemi – økt risiko for infeksjon

Musculoskeletal system Redusert muskelmasse

Osteoporose

Risiko for frakturer og dislosering under anestesi

Thermoregulation Redusert muskelmasse Vasodilatasjon, redusert terskel for å

skjelve

Hypotermi – risiko for infeksjon, koagulopati,

arytmi, MI

Liver Redusert blodstrøm Redusert oksidering Redusert metabolisme av noen legemidler

Physiological aging + anesthesia and surgery = increased risk

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 funcTon↓)

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

26

Forventet gjenstående levetid

Walter LC, JAMA 2001

Remaining life expectancy

WHAT ARE THE TWO MAJOR

DETERMINANTS OF 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 crucial to

maintain health

Arking, The biology of aging, 3rd ed

• Biomarker should be able to function 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

Potential biomarkers of aging

Journal of Geriatric Oncology 2014;5:204–218From Marije Hamaker

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)

Take home messages

• Ageing leads to a physiological decline

• Individual differences more marked withincreasing age

• Associated challenges, such as lack of clinicaltrials and lack of social network

• Chronological age matters – but is only one ofmany factors to consider in treatmentdecisions