The Biology of Aging – Week 1

Chong He, PhDCHe@buckinstitute.org

Jan 11, 2018

• Why do we need to study aging?

• How to evaluate our information?

Basic Statistic

Today’s topic

Why aging is an issue?

Kathleen Casey-Kirschling

United States age structures over time

$5,009TRILLION

$3,660TRILLION

$2,807TRILLION

$2,298TRILLION

2007 2012 2017 2022

% of GDP Expenditures

16.4%17.9%

18.4%

19.9%

Source: “National Healthcare Expenditure Projections 2012-2022 Table 1: National Health Expenditures and Selected Economic Indicators, Levels and Annual Percent Change: Calendar Years 2007-2022.” U.S Department for Health and Human Services-Centers for Medicare and Medicaid Services, Office of the Actuary. January 2013.

The facts

We are Living Longer

Life expectancy throughout history

National Center for Health Statistics

1776 35

The rate of healthspan has not gone up to match the rate of lifespan

Biology of Aging, McDonald

Biology of Aging, McDonaldAging-related diseases

Aging is the major risk factor for chronic diseases and loss of resilience

Genes Environment

Aging is the major risk factor for chronic diseases and loss of resilience

Genes Environment Genes Environment

Aging

Young Old

Aging is the major risk factor for chronic diseases and loss of resilience

Genes Environment Genes Environment

Aging

Young Old

Genes x Environment = G x EAging x A x = AGE

Aging is the major risk factor for chronic diseases and loss of resilience

Risk factors for Cardiovascular DiseaseCholesterol, obesity and the usually suspects (smoking, exercise, diet…)

+

+

=

=

Risk factor for Cardiovascular Disease (Framingham Heart Study)

Circulation. 2008 Feb 12;117(6):743-53.

Alzheimer’sAmyloid plaques on autopsy

Adapted from : Practical Neurology 2012;12:88–96.

Aging itself is the major risk factor for chronic diseases

Miller RA. Milbank Q. 2002;80(1):155-74.

AGINGStroke

Arthritis

Cataracts

Frailty

Heart Disease

Type IIDiabetes

Cancer

Neurodegeneration

Aging is a driving force in chronic disease

3.5 years↑

The Challenge:Chronic diseases are studied individually

Alzheimer’s Disease

Arthritis

Macular Degeneration

Immunity

Sarcopenia

Diabetes

Vascular Disease

Hearing

Cancer

Chronic Kidney Disease

COPD

Biology of Disease

NIANIAMS NHLBI

NIDCD

NIDDK

NCINHLBINIAID

NIAMS

NIAMS

NIDDK

Curing one disease at a time leads to increase morbidity

Young

Disease 1

Disease 2

Curing one disease at a time leads to increase morbidity

Young Old

Disease 1

Curing one disease at a time leads to increase morbidity

Young Old

Disease 1

“Expenses for people with one chronic condition were twice as great as for those without any chronic conditions. Spending for those with five or more chronic conditionswas about 14 times greater than spending for those without any chronic conditions.”

Agency for Healthcare Research and Quality (AHRQ)The High Concentration of U.S. Health Care Expenditures, Research in Action, Issue 19

Re-thinking the basics

• Age-related chronic diseases and functional decline are the biggest challenges of the 21st

century.• Aging is, by itself, the biggest risk factor for the

increase in chronic diseases , and the decrease in resilience.

• Resilience in older age is the ability to stand up to adversity and to 'bounce back' or return to a state of equilibrium following individual adverse episodes.

• Thus, addressing aging will provide the biggest impact, by addressing multiple age-related health issues at once!

• I ALREADY KNEW that aging is the major risk factor for diseases….

• But I can not change my age!

Big Deal !!!

Division Name City Chip Elapsed Time

Pace Gender Age Age Place

Half Marathon

Chong He

Novato 02:12:08 10:05 F 32 162 of 423

Half Marathon

NealDempsey

San Francisco

02:12:08 10:05 M 74 1 of 3

Longer healthspan

Birth

Birth

Birth

Death

Death

Death

Morbidity Onset

Morbidity Onset

Morbidity Onset

DISEASE APPROACH

EXTEND HEALTHSPAN

Novel strategy: extend healthspan

Extend lifespan but not healthspan

Extend healthspan and lifespan

There is a disconnect between the goals of medicine and the goals of the elderly

Cardiovascular Disease(CVD)

Stroke

Cancer

Diabetes

Respiratory

Accidents

InfectionsKidney

Alzheimer’s

Causes of Death

Arthritis

Back Pain

CVD

Mental Health

Diabetes Respiratory

Stroke

Hearing

Blindness

Causes of Disability

What makes you “old”?

Pew Research Center 2009

Predictions about elderly life

Pew Research Center 2009

• Physical:Starvation

Water deprivation

Sleep deprivation

Physical restraint

Heat stress

Cold stress

Trauma/surgery

Exercise

Measuring Resilience

• Chemical:

Anesthesia

Chemo

Paraquat

Radiation

Inflammation

Infection

Hypoxia

Re-focus from Cause-of-Death to Healthspan

• Aging is the major risk factor for most chronic diseases and loss of function, and it is malleable.

• Geroscience: is an interdisciplinary field that aims to understand the relationship between aging and age-related diseases.

• The geroscience hypothesis posits that addressing basic biology of aging will result in better health than addressing each disease individually.

Take home message

• Unified China

• Great Wall

• Terracotta Army

Qin Shi Huang (秦始皇) (259 BC –210 BC)

Age categories:World Health Organization TextElderly 60 – 75 young-old 65-74

Old 76 - 90 old-old 75-84

Very Old Over 90 oldest old 85+

• 1957 – NIH established the Center for Aging Research• 1974 – National Institute on Aging established

Gerontology – broad study of the aging process

Geriatrics – medical specialty concentrating on health problems associated with getting older

Centenarian- a person who is 100 years old or older

Supercentenarian - a person older than 110 (1:1000 centenarians become super centenarians)

The Buck: the leading research institute for the

Geroscience era

Buck InstituteFirst Independent Research Institute on Aging (1999)

What is the maximum human lifespan ?

Maximum life span: Jeanne Calment (1875-1997), was a French supercentenarian who has the longest confirmed human lifespan, living to the age of 122 years, 164 days.

https://en.wikipedia.org/wiki/List_of_oldest_living_people

Oldest living people: https://www.youtube.com/watch?v=GVw98d8j2rA

1995Age 65: ~1.5 more women than menAge 85: ~2.5 more women than men

2002Age 65: ~1.2 more women than menAge 85: ~2.2 more women than men

Women live longer on average

• Men are more abusive of their bodies. Factors such as smoking, drinking, and overeating, life threating events.

• Having two X chromosomes, women keep double copies of every gene, meaning they have a spare if one is faulty. Men don’t have that back-up.

• The grandmother hypothesis states that as mothers age, the costs of reproducing become greater, and energy devoted to those activities would be better spent helping her offspring in their reproductive efforts.

Longevity limit?

Longevity limit?

Venture capitalist Dmitry Kaminskiy thinks he has what it takes to lengthen people’s life spans: a million-dollar prize, which he will award to the first person to beat the current longevity record and reach his or her 123rd birthday.

Video

Longevity Genes_ Nir Barzilai, M.D.

Week 1: Introduction and course overview; basic statistic concept

Week 2: Aging study in model organisms; genome editing tools

Week 3: Aging theory I: calorie restriction; diet and microbe

Week 4: Aging theory II: DNA damage, senescence, biology clock

Week 5: Stem cell and regenerative medicine in aging study

Week 6: Reversing aging with drugs

• Aging is the major risk factor for most chronic diseases and loss of function, and it is malleable.

• The geroscience hypothesis posits that addressing basic biology of aging will result in better health than addressing each disease individually.

Take home message

Resilience in older age is the ability to stand up to adversity and to 'bounce back' or return to a state of equilibrium following individual adverse episodes.

Geroscience – is an interdisciplinary field that aims to understand the relationship between aging and age-related diseases.

Gerontology – broad study of the aging process

Geriatrics – medical specialty concentrating on health problems associated with getting older

Centenarian- a person who is 100 years old or older

Supercentenarian - a person older than 110 (1:1000 centenarians

become super centenarians)

Definitions

We don’t want to kill death, we just want to temporarily disable it.

What would you do for ten more healthy years?

Basic Statistic

News---Study: Cereal Keeps Girls SlimGirls who ate breakfast of any type had a lower average body mass index, a common obesity gauge, than those who said they didn't. The index was even lower for girls who said they ate cereal for breakfast, according to findings of the study conducted by the Maryland Medical Research Institute with funding from the National Institutes of Health (NIH) and cereal-maker General Mills.[…]The results were gleaned from a larger NIH survey of 2,379 girls in California, Ohio, and Maryland who were tracked between the ages of 9 and 19.[…]As part of the survey, the girls were asked once a year what they had eaten during the previous three days.

Sept 8, 2005

Observational Study Experimental Study

• collect data in a way that does not directly interfere with how the data arise, i.e. merely “observe”

• can only establish an association between the explanatory and response variables

• if an observational study uses data from the past, it’s called a retrospective study, whereas if data are collected throughout the study, it’s called prospective.

• randomly assign subjects to various treatments

• can establish causal connections between the explanatory and response variables

Correlation Causation

Observational Study Experimental Study

News---Study: Cereal Keeps Girls SlimGirls who ate breakfast of any type had a lower average body mass index, a common obesity gauge, than those who said they didn't. The index was even lower for girls who said they ate cereal for breakfast, according to findings of the study conducted by the Maryland Medical Research Institute with funding from the National Institutes of Health (NIH) and cereal-maker General Mills.[…]The results were gleaned from a larger NIH survey of 2,379 girls in California, Ohio, and Maryland who were tracked between the ages of 9 and 19.[…]As part of the survey, the girls were asked once a year what they had eaten during the previous three days.

Sept 8, 2005

Correlation or Causation?

Three possible explanations

1. eating breakfast causes girls to be slimmer

2. being slim causes girls to eat breakfast

3. a third variable is responsible for both

?

Being health conscious

Correlation does not imply causation

Sampling

• Wouldn’t it be better to just include everyone and “sample” the entire population, i.e. conduct a census?

• We would never eat a whole pot of soup just to check its taste, after all. When you taste a spoonful of soup and decide the spoonful you tasted isn't salty enough, what you're doing is simply exploratory analysis.

The Literary Digest, polled about 10 million Americans and got responses from 2.4 million

Lose with 43% of the votes

Election results Win with 62% of the votes

Sampling

• If the soup is not well-stirred it doesn't matter how large a spoon you have, it will still not taste right.

• If the soup is well stirred, a small spoon will suffice to test the soup. it's important for our sample to be representative.

Principles of experimental design

• control: Compare treatment of interest to a control group.

• randomize: Randomly assign subjects to treatments.

• replicate: Within a study, replicate by collecting a sufficiently large sample, or replicate the entire study.

Experimental Study

• placebo: fake treatment, often used as the control group for medical studies

• placebo effect: experimental units showing improvement simply because they believe they are receiving a special treatment

• blinding: when experimental units do not know whether they are in the control or treatment group

• double-blind: when both the experimental units and the researchers do not know who is in the control and who is in the treatment group

Experimental design terminology

• My neighbor : “My brother gave me this tea and he said after drinking one month he started to grow new dark hair. So I have tried it for one month and I saw dark hair too. You should try this tea. It helps you grow dark hair. ”

Case study

Tea dark hair

How to test?

• Correlation is not equal to causation. • How to test causation?• Think critically about your sample.

Take home message