Transcript Death and rebirth of the oxidative damage theory of aging

The Prospects that
Emerging Science
Offers Us for
Long Healthy Lifespans
PART 2
October 7, 2014
Great Presenter Series
Wayland Public Library
Actions and interventions for
extending healthspan and
lifespans
– Focus on the personal and
practical
Vince Giuliano
www.agingsciences.com
PART 2 OF
The Prospects that Emerging Science
Offers Us for Long Healthy Lifespans
Actions and interventions for
extending healthspan and lifespans
– Focus on the personal and practical
SCIENCE BASED
ANTI-AGING
INTERVENTIONS
First: the stakes:

Want to greatly up the probability of 10-20 extra
good healthy and productive life for yourself or a
loved one?
If we could delay aging an average of 10 years the health care
cost savings would be immense
Everybody moves
back 10 years on
the health care
cost curve
Plus, the economic productivity benefits of everyone working
10 years more could be worth trillions

ALL the animal longevity experiments show that
lifespans and healthspans go together
◦ Double the lifespan of an animal and they will still die
of the same causes and diseases
◦ They will get the diseases and die of them much later.
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This leads to a whole different way of thinking
about degenerative diseases.
Aging now thought to be not only a risk
factors for age-related diseases but a
causal factor for such diseases.
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:Health care” in aging now mainly means trying to
repair degenerative diseases and processes after
they have happened – cancer, diabetes, dementia,
heart disease etc.
By the time these are diagnosed it is usually too
late to fix them
Most such diseases are the results of 10-20 year
processes; they can be seen coming
It is far easier and less expensive to slow or stop
these diseases from happening than to try and fix
them after the fact.
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From repair-shop focus
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To lifestyle design and
preventative maintenance
focus
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Several aging interventions have worked in more
primitive animals:
◦ C-elegans, extending lifespans by a factor of up to 8
◦ Drosophila melanogaster
◦ Mice and rats, up to almost double
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Often these have required interventions not
practical for humans
◦ E.g. genetic interventions
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DEMONSTRABLY EXTENDED HEALTHSPANS AND
LIFESPANS BY A FACTOR OF FOUR.
Happened over a 40 year period
We can apply the approach personally
Was it in:
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C-elegans?
Drosophila melanogaster?
P66shc- knock-out mice?
Naked mole rats?
CARS!
I learned
to drive
in this
car.
1950 Chevy Bel Air, like my grandmother’s:
actual lifespan 3.8 years, 38,000 MI
1959 Studebaker
Lark, like my first
new car. Lifespan
3.4 years, 28,900
miles
The first 2 new cars that I purchased
Both great lookers, impressed the
ladies in the first year before they
rusted and fell apart.
My existing 2005
Subaru, 10 years old
with 100,000 miles.
Good for another 10
years and another
100,000 miles
No rust
runs like new
28-26
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The breakthrough was not a single scientific or
technical leap forward
It was in a process called Total Quality
Management (TQM) that was pioneered for autos
by Toyota, that eventually US auto companies had
to pay attention to as well
TQM called for constant attention to process, to
learning, and an ongoing commitment to
incremental improvements, year after year
So cars today are different in thousands of ways
than they were 49 years ago
WE CAN INDIVIDUALLY
ADAPT THE SAME GENERAL
TQM APPROACH TO
CONSTANTLY IMPROVE OUR
HEALTH AND LONGEVITY
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EXTENDING HUMAN LIVES DIVIDES INTO TWO QUESTIONS
1. WHAT CAN WE DO TO EXTEND AVERAGE HUMAN
LIFESPANS 10-20 YEARS, FURTHER
RECTANGULARIZING THE SURVIVAL CURVE BUT
RESPECTING THE 122 YEAR HUMAN AGE LIMIT?
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We know that some people live 10-20 years more than
others. How can we move the general population to living
the longer lives?
2. WHAT MIGHT WE DO TO BREAK THROUGH THE 122 YEAR AGE
LIMIT SO PEOPLE CAN LIVE 150 OR HUNDREDS OF YEARS?
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Woah! This would mean breaking some very basic rules.
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Yet. I believe it may well be possible
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I save this second question for another talk
Speeding up the process of adding another 10-20 years to our
lifespans is probably entirely achievable – further
rectangularizing the life expectancy curve
Applying conventional wisdom about health can go a long
ways in this direction, even for older adults
•For most people, genetic background need NOT be a
major factor (more on this later)
•It can be done by paying attention to lifestyle, diet,
exercise, stress management, the judicious use of
plant-based dietary supplements
•Pharmaceuticals and a new generation of
nutraceuticals now in the pipeline might also help
PRACTICAL SCIENCEBASED HEALTH AND
LONGEVITY
PRACTIVES AND
INTERVENTIONS
This is very tough to do.
However, extending human lifespans
is an easier challenge
- On both the societal an personal levels
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As biological entities, evolution (God) has designed
us with significant adaptability and potential for
further evolution
In fact, we are probably evolving faster today than
at any point in history
◦ Biological and social evolution are feeding oneanother
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I believe that by taking advantage of these
adaptability features we can continue to extend our
lifespans, both individually and as a society
CURRENT RESEARH
FINDINGS
CONTEXT OF THE
POSSIBILITY OF LONG
HEALTHY LIVES
TRADITIONAL
AND CURRENT
FOLK
MEDICINE
FACILITATING
TECHNOLOGY
UNDERSTANDING
LEADING TO
INDIVIDUAL
ACTIONS
BASIC ADAPTIBILITY OF
HUMAN BIOLOGY
PUBLIC HEALTH
INITIATIVES
POSSIBILITY OF
EXTENDING
LIFESPANS BY 1520 MORE YEARS
• I believe going for that extra 10-15 years is now
largely a personal choice, of being one of those who dies
sooner, or one of those who dies later.
• Not everybody knows they have that choice.
• Picking the longer lifespan requires learning and
following some rules with discipline
• The important fact to keep in mind is that to get
to live to age 160 or more, it is necessary to live to
100 first.
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In part a matter of conventional wisdom, e.g. advice of
popular book and TV gurus
◦ Regular exercise
◦ Good rhythms of sleep and rest
◦ Rich social, intellectual and physical life
◦ Attention to stress management
◦ Careful attention to diet
◦ Use of dietary supplements
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However, in the last three categories there is
also important unconventional wisdom
STRESS
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Avoid
Not exactly. Think again!
You need and can benefit from stress
But you need to manage stresses and keep them
within limits
The body of science involved is called
hormesis
“Was mich nicht umbringt,
macht mich stärker
Friedrich Nietzsche
“What does not
kill me, makes
me stronger”
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Hormesis is about stress and
how organisms adopt to deal
with stress.
Organisms are shaped and
limited by the stresses they
encounter in their environments.
So, biological substructures and processes are
adapted to function best under the stress conditions
they normally experience.
Organisms have evolved so they function best with
certain amounts of key stresses, not in the absence
of stresses.
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Biological systems react to stress in a
nonlinear fashion so as to restore
balance.
The essence of hormesis is that, within a
certain quantitative “window” of amount
of stress, any biological organism and its
subsystems mount strong defenses and
as a result is better off with some stress
than if there were no stress at all.
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At high doses stresses
create damage
At low dose levels,
stresses promote body
defenses that make
you stronger and
healthier
Hormesis has a
dual character
Risk,
Damage
Health
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the horizontal axis depicts level of applied stress, say as
driven by ROS load in a cell.
The vertical axis represents relative risk, level of probable
pathological organism response where normal level is 1.
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Some familiar examples of hormesis
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Immunization by vaccines
Ischemic preconditioning;
“Grit” training
Exercise training
Radiation hormesis
No
risk
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It is time to stop thinking of stressors like ROS,
heat, cold, various hormones and pathways as
“good” and “bad,” and instead to start thinking of
how they work in terms of the hormetic doseresponse curve.
The hormesis pathways have a lot to do with longevity of
individuals and of species
Experiments with lower species indicate that lifespans of lower
species can be enhanced via inducing hormesis, e.g.
•Drosophila via repeated application of
mild heat stress
•Multiple stressors in Caenorhabditis
elegans
•Up to 40% life exension in C-elegans
due to heat shock
•Multiple species via calorie restriction
•Multiple species via radiation
Image source
Bristle cone pines is the world’s longest-lived non-clonal
species, with livespans of up to 5,000 years
•Grow on mountains between 5,600 and
11,200 feet, White Mountains, California
•Subject to strong and highly variable
stresses: cold temperatures, dry soils,
high winds, short growing seasons, and
constant hypoxia
•Water/moisture stress a major factor
•Very disease resistant
•Needles alone may last 40 years
The naked mole rat lives eight times as long as comparable-size
mice and can live up to 30 years
 Lives in conditions of hypoxia, high carbon dioxide,
acidification, excrements, urine, wars between colonies
•Shows little decline due to aging, maintains high
activity, bone health, reproductive capacity, and
cognitive ability throughout its lifetime.
•Never get cancers, the main killer of mice
•Has incredible hypoxic response. Can withstand
brain oxygen deprivation for more than 30 minutes
• Exhibits mutation in the specificity of HIF1a
•Has six times the amount of endogenous expression
of the hormetic anti-oxidant defense protein Nrf2.
•Has high endogenous levels of NRG-1, P16
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Compared with other mammals of similar size, bats live a
long time, with lifespans of between 20 and 40 years.
Rats live between 2 and 3 years, on average
Despite living in dank, dark, dung-filled caves, bats only
rarely get sick or are debilitated by infections
Out of more than 5,000 types of mammals on the planet,
bats are the only one capable of sustained flight and
some species can fly more than 1,000 km in a single
night.
Such exertion entails great free radical stress
Bats have evolved to have powerful free radical defenses
and DNA repair systems
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Raises the questions:
◦ What role do repeated hormetic stress experiences
play in the longevity of very long-lived species?
◦ Are there additional ways for us to use hormesis so
we can live longer and healthier?
Or, lack of stress?
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The key is not
avoiding stress; it is
managing stress
This means
welcoming the
stresses of life – they
help us live longer
It also means making
sure that they lie
within the personal
hormetic ranges
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The stresses that can
be managed include:
◦ Heat and cold
◦ Exercise, necessary
within limits
◦ Endurance-demanding
activities
◦ Intellectual challenges
◦ And lots of
others
In the course of a typical day, we have numerous minor hormetic
experiences, e.g. me Feb 13, 2013
•Cold semi-naked in bedroom and bathroom morning –
cold shock pathway
•Blueberries, walnuts and phytosubstances supplements
for breakfast– Nrf2 pathway
•Frustration stress related to a computer help line
conversation – cortisol, multiple pathways
•Minor fight with my wife - same pathways
•Exercising/shoveling snow/treadmilling – PGC1 pathway
In the course of a typical day, we have numerous minor hormetic
experiences, e.g. me Feb 13, 2013 (continued)
• Chain sawing, fumes, gas spilled on my hand – Nrf2
pathway - phase II detoxifying enzyme genes via
AREs.
• Pepperoni snack containing nitrites – same pathway
• More plant-based supplements during day
• Supper included salmon with olive oil, garlic, ginger,
oregano and a touch of pepper sauce, broccoli and
mixed greens – After supper, for desert I munched
on 80% coco chocolate – Nrf2 path again
• Bedroom/bathroom icy cold again at night – cold
shock again
Practical personal stress management to keep it hormetic
Stress management
techniques known to
be effective
Image source
DIET
AND DIETARY
SUPPLEMENTS
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Plant-based Mediterranean diets best – fresh
vegetables and fruits, fish
Minimize intake of sugar or simple carbohydrates
that turn to sugar
Avoid saturated fats, burnt foods
Better smaller meals earlier in the day
The same advice as for avoiding diabetes, insulin
resistance, cardiovascular problems, cancers,
neurological diseases, etc..
Supported by much research: pathway
studies, animal studies as well as human
epidemiological studies.
E.g. Take advantage of plant-based substnces
and the Nrf2 molecular pathway
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Nrf2 is a gene transcription factor. It has to do with
what genes are turned off or on.
◦ Nrf2 appears to be a master regulator of cellular responses
to oxidative damage and other stressful conditions.
◦ When Nrf2 is activated it turns on some 240 healthproducing genes.
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These genes activate the body’s own powerful
antioxidant responses, inhibit excess inflammation,
inhibit cancer progression, detoxify poisons, etc.
Nrf2 can be turned on by many plant-based foods that
contain certain phytochemicals, and by taking dietary
supplements that contain those phytosubstances
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Anthocyanidins: (Cyanidin, Delphinidin, Malvidin,
Pelargonidin, Peonidin, Petunidin) Red, blue, and purple
berries; red and purple grapes; red wine
Flavanols: (Catechin, Epicatechin, Epigallocatechin Epicatechin
gallate, Epigallocatechin gallate), Teas (particularly green and
white), chocolate, grapes, berries, apples, black and oolong)
Theaflavins: (Thearubigins, Proanthocyanidins ) Chocolate,
apples, berries, red grapes, red wine
Flavanones (Hesperetin, Naringenin, Eriodictyol) Citrus fruits
and juices, e.g., oranges, grapefruits, lemons
Flavonols (Quercetin, Kaempferol, Myricetin, Isorhamnetin)
Widely distributed: yellow onions, scallions, kale, broccoli,
apples, berries, teas
Flavones (Apigenin, Luteolin) Parsley, thyme, celery, hot
peppers
Isoflavones (Daidzein, Genistein, Glycitein) Soybeans, soy
foods, legumes
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For example, many have other gene-activating
(epigenetic) health-producing activities including:
◦ Activating DNA repair genes
◦ Inhibiting inflammatory pathways
◦ Changing DNA conformation to ensure that protective
anti-cancer genes are expressed
◦ Embedding their plant RNA in your RNA to make sure
you remain protected
◦ Creating stress signaling (hormetic response) in cells
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Nrf2 expression is clearly associated with control of aging in a
number of species. It is particularly high in certain long-lived
species.
Increasing Nrf2 expression can help prevent, ameliorate or clear
up numerous age-related health problems in a variety of species,
problems ranging from Type 2 diabetes to ischemic stroke, to
cancers to cardiovascular problems to recovery from physical
injuries.
To the extent diseases or conditions of infirmity can be
prevented or cured people will live longer. “Longevity is the art of
not dying.”
Nrf2 is an example of a longevity pathway. There are many other
longevity and shortivity pathways to be considered
Individuals can likely live longer by learning more about what
science has now to say about diet and the health effects of
plant-based substances
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Key longevity-related molecular pathways
◦ The mTOR pathway
 Inactivated by the drug Rapamycin
◦ The Klotho pathway
 Klotho is an anti-aging and disease-combatting gene and
protein
◦ The IGF1-FOXO3 pathway
 Moderated by exercise, sirtuins, resveratrol and
resveratrol analogs
◦ Modulating these has extended lives of small animals
◦ Mostly, interventions not practical for humans
 E.g. genetic interventions
◦ Personally I doubt that these will get us significantly
further than the interventions already mentioned.
◦ They certainly won’t get us beyond the 122 year limit
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Be sure that you consume adequate amounts of trace
micronutrients including selenium, lithium, potassium,
and chromium
Switch to using extra-virgin olive oil instead of
commercial bottled salad dressings
If your offices in your home locate it in the top or
bottom floor so you will climb lots of stairs
In your daily exercise regimen, include 5 minutes of
strenuous movement that elevate your hear rate
Incorporate stretching and movement exercises that
affect your limbs, torso, etc
While sitting at your desk working, get up and walk
around, climb some stairs, every hour or two.
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Keep your intellect fully engaged; take on some very
basic challenge like, for example, staying young
Remember, that the best defensive phytochemicals tend
to concentrate on the outside surfaces of fruits and
vegetables, Don't scrape them off and be sensitive to
color:
Eat dark green salad vegetables instead of white ones;
small deep purple wild blueberries instead of giant pale
red strawberries, broccoli instead of
Maintain a regular pattern of sleep
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On every possible opportunity, bias your eating towards
more healthy alternatives. This could include using
more extra-virgin olive oil, eating more broccoli, or
ordering an avocado salad
Eat a healthy breakfast. Mine consists of stone ground
oatmeal, blueberries, walnuts, soy milk, and espresso
coffee
Maintain a rich family and social life
Enjoy good sex when it is right for you
Be on the constant lookout for additional enhancements
as they present themselves
It is the little day to day decisions that really count!
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Use every opportunity to see how well you are doing
◦ Conventional medical measurements of health states:
lipids, CRP, physical exams, etc.
◦ Electronic movement and exercise tracking, e.g. FITBIT,
weight, BMI, etc
◦ Select among new Apple, Samsung and Google Android
health and fitness mobile tracking apps, There are
thousands of them
◦ New sophisticated consumer devices and Apps are coming
out at a very rapid rate (cell phone features, smart watches,
etc.)
 Be an early adapter in this emerging technology
development
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Participate in health-oriented communities
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Improving your personal lifespan and health
condition is possible
◦ You may be able to beat the average by 10-20 years
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Do not expect this to happen via a medical
breakthrough or a pill
It requires a commitment to constant learning
about yourself and what science tells us
And a commitment to applying that knowledge to
your own circumstances
Aging Science core team:
James P. Watson, M.D.
Melody Winnig, M.I.S.
Michael Winnig, M. C.
Vince Giuliano, Ph.D.
With many Associate Researcher/Writers
www.agingsciences.com