Transcript Death and rebirth of the oxidative damage theory of aging

The Prospects that Emerging Science
Offers Us for Longer Healthy
Lifespans
March 26, 2013
Kopriva Lecture
Montana State University
Presentation by:
Vincent E. Giuliano, Ph.D.
Agingsciences.com
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State of the sciences of aging
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Some important things we know about aging
◦ Consequences of aging
◦ Aging, diseases and healthspan
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What about extending human lives?
◦ Possible societal benefits
◦ Epigenetics
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Practical steps for Living 10- 20 years longer
 Conventional wisdom
 Focus on diet – Nrf2 pathway
 Focus on stress management – hormesis
◦ Breaking through the 122 year age limit
 Stem cell science
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Understanding
aging takes us
into just about
every area of
human biology
and medicine
Image source
Growth in PubMed.org publications
Now around 20.5 million indexed
research
publications
More than a
million new
publications
every year
Composite network of molecular pathways active in HCV-infected liver tissue.
Purine metabolism – image source
Image
source
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There are thousands of such diagrams to be found in the
literature not all consistent, mostly unconnected with other
related diagrams
The research tends to be solid but extremely complex.
Because of this, researchers in one field usually don’t follow
the literature in possibly-related fields.
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Understanding aging takes us into just about every
area of human biology and medicine
The field is incredibly broad and deep
It consists of many disparate areas of studies
Most scientists are only partially aware of what
other scientists producing related results are
doing, or are unaware
So, what is presented here is
story
my own
of what is known about aging
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AMOUNT AND DEPTH OF DETAIL IS ASTOUNDING –
A HUMAN IS BY FAR THE MOST COMPLEX ENTITY
KNOWN IN THE UNIVERSE
LIKE PUTTING TOGETHER A 30 MLLION PIECE
MULTIDIMENSIONAL JIGSAW OF AGING AND THE
PATHWAYS INVOLVED IN AGING
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WE ARE ASSEMBLING SUB CHUNKS OF THE PUZZLE WITHOUT
KNOWING HOW THEY WILL ALL EVENTUALLY FIT TOGETHER
◦ WE DON’T HAVE A GUIDING PICTURE ON THE BOX COVER

WE HAVE ENOUGH BIG SUBCHUNKS TO MAKE MANY OF US
THINK THAT THE PUZZLE WILL BE COMING TOGETHER SOON
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WE UNDERSTAND A LOT ABOUT THE CONSEQUENCES OF
AGING AND THE PATHWAYS INVOLVED IN AGING
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We are living longer
Survival
curve is
becoming
rectangular
Image source
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It is fatal
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Everybody so far dies by age 122
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Efficiency and regulation of key body
systems declines with advancing age
◦ Stem cell senescence and decreased
cell differentiation capability
◦ lessened immune responses
◦ Decline in key hormones
◦ Decreases in numerous key proteins
◦ Decreased antioxidant defenses
◦ Decreased DNA repair capabilities
◦ Metabolic pathways less efficient
◦ DNA gets methylated
◦ Histones get deacetylated
◦ Molecular signaling pathways
becomes less efficient
◦ Activation of key health genes
decreases
◦ Activation of cancer and other
disease-related genes increases
◦ More and more DNA damage
The list goes on and on
Incremental
deecripitude!
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Consequences of aging
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Cancers, cardiovascular diseases, diabetes,
Alzheimer’s Disease, Parkinson’s Disease, etc.
Alzheimer’s Disease
Image source
Image source
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Consequences of aging
With aging there is a steep rise in
susceptibilities to age-related
diseases, e.g. cancers
Image source
The aged consume far greater health care resources
Cost of fall injuries by age group
Image source
Image source
A growing
world-wide
problem
Image source
◦ The theories and views of aging and stream of new
discoveries give many clues as to how to extend
human lives
◦ Having us live longer lives is an easier matter to
grapple with than fully understanding aging (which
probably requires fully understanding biology)
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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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An important observation of all the animal
longevity experiments is 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.
•Suggests a shift in research
strategy from seeking cures of
diseases of old age to research
focused to slowing aging and
delaying onset of such diseases
•This could make a lot of sense
because progress in curing
degenerative diseases of old age
has been extremely slow. Despite
spending hundreds of billions on
research on them over many
decades
If we could delay aging an average of 10 years the economic
health care and increased productivity benefits would be immense
Everybody moves
back 10 years on
the health care
cost curve
Image source
Social security act passed 1935
Average US life expectancy 64
Now. Average US
life expectancy 80.5
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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 ourselves individually and
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.
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, and the judicious use of
plant-based dietary supplements
•Pharmaceuticals now in the pipeline could also help
• 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 interventions are simple but involve patterns of
gene activation – they have epigenetic impacts.
◦ Once not very long ago we thought that once we
sequenced the genes in the human genome we would
be ready to understand biology, diseases and aging.
◦ After all, genes make our proteins, and that is what
we are all about
We were wrong
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We now know that the genes in the nucleus of a cell contain
only a small portion of the information there in the DNA.
The rest of the information controls which genes are activated
and when. It is called epigenetic information
◦ After all, all the cells in a body contain the same genes.
◦ And most of our genes are the same as those in mice or apes
◦ In both cases the differences are mainly due to which genes are
activated
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Gene activation patterns change throughout life and with aging
So, more and more researchers now grasp that we need to go
far beyond genetics to epigenetics to understand what is going
on in biology and aging.
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In the long sequences of DNA between genes, once thought
to be “junk DNA” (ncRNA coding)
In how genes are silenced by being methylated
In how tightly DNA is wrapped around the spindles
(histones) in cells (histone acetylation)
Compared to some 25,000 genes there are millions of
epigenetic marks. Most remain unknown.
Epigenetics is providing a whole new way of looking at
biology, diseases and biology
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Mostly a matter of conventional wisdom, e.g. advice of
popular book and TV gurus like Dr Oz.
◦ Regular exercise
◦ Good rhythms of sleep and rest
◦ Rich social, intellectual and physical life
◦ Careful attention to diet
◦ Use of dietary supplements
◦ Attention to stress management
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However, in the last three categories there is
also important unconventional wisdom
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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
Minimize meat consumption
Better smaller meals earlier in the day
Pay attention to omega-3 vs omega-6 balance
The same advice as for avoiding diabetes, insulin
resistance, cardiological problems, cancers,
Supported by much research: pathway
studies, animal studies as well as human
epidemiological studies.
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Nrf2 is a genetic transcription factor. It has to do with
what genes are turned off or on (epigenetic activation).
◦ 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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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.
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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 sure that protective
anti-cancer genes are expressed
◦ Embedding their plant RNA in your RNA to make sure
you remain protected
◦ Creating stress signaling (hormetic responses) in cells
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Avoid
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Not exactly. Think again!
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You need and can benefit from stress
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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 starker.”
Friedrich Nietzsche
“What does not
kill me, makes
me stronger”
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Organisms have evolved so they
function best with certain amounts
of key stresses, not in the absence
of stresses.
◦ Organisms are shaped and limited by
the stresses they encounter in their
environments.
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Hormesis is about stress and how
organisms adapt to deal with stress.
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 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
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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It applies to virtually all biological
organisms on the levels of cells, organs
and whole organisms
It applies to all known forms of stress, e.g.
◦ Radiation, Inflammation, Exercise, Cold. Heat
◦ Dietary restriction, Absence of key nutrients
◦ Blood flow restriction, Pathogens, oxidative
stress, Mental/emotional stress
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It operates through multiple well-studied
biological pathways
◦ The Nrf2 pathway is one of them
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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
Dose response is critical – the general curve seems to
always apply though its quantitative parameters will
vary widely
1.
Timing and duration of stressor is critical.
2.
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Cannot be for too long.
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Works best when synchronized with circadian time
windows
For hormetic behavior, stressors must be pulsed;
cannot be constant.
3.
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Periods of rest and recuperation essential.
4. Stress responses are limited by stress pathways
activated;
Multiple stressors may produce no better responses
than single ones
5. Repeated cycles of hormetic stress changes
parameters of stress response curve and makes
organism capable of handling higher and higher
levels of stress
E.g. exercise training, high-altitude accommodation
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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
◦ 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
•Trying to figure aging and biology out – BDNF and
related pathways.
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
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Key longevity-related molecular pathways
◦ The mTOR pathway
 Activated 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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The answer, if any, will lie in integrative newscience approaches beyond conventional wisdom
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Molecular biology
◦ study of biology at a molecular level. Overlaps
with biology, chemistry, genetics and
biochemistry.
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Epigenetics/Epigenomics
◦ Critical information not in the genes themselves
◦ Gene activation pathways
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Hormesis again
◦ Lessons of long-lived species
Stem cell science
◦ Induced pluripotent stem cells
◦ Adult somatic stem cells, autologous stem cells
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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A major body of research in recent years has been
Induced Pluripotent Stem Cells (iPSC): creating them,
engineering them for practical applications, applying
them for regenerative medicine
An iPSC is functionally almost exactly like an embryonic
stem cell that can be created for an individual by
chemically/transcriptionally reverting any normal body
cell back to “pluripotent” state
Technologies are being perfected for taking a skin or
blood cell, reverting it back to iPSC status, multiplying
it, and then inducing it to differentiate into particular
body cells, like heart cells, liver cells, blood cells, etc.
These cells are being experimentally used in animals to
regenerate organs
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Cells derived from iPSCs might
be used for many kinds of
disease cures
Image soiurce
Cells derived from iPSCs are
patient’s own cells and will
not face immune system
rejection
Image source
The Stem Cell Supply Chain
APOPTOSIS
Diseases, aging,
death
APOPTOSIS
FEWER
Less aging, diseases,
Longer lives
Closing the loop in the stem cell supply chain could conceivably lead to
longer lives. Hopefully this could be induced inside the body.
Proposed in 2010. Steady research progress since then.
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HORMESIS
◦ Multifactorial hormesis - the theory and practice of maintaining health and
longevity, Sarcopenia - the Age-related Los of Muscle Mass and Function Part I: Pathways and factors,
◦ The Hormetic Wild Animal Zoo and Their Zookeepers,
◦ Mitohormesis,
◦ Radiation hormesis,
◦ Mitochondria Part 2: Mitochondrial Responses to Stress: Mitochondrial
Signaling: Survival and Death Pathways,
◦ Hormesis and age retardation
NRF2 PATHWAY
◦ The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative
damage and generation of hormetic effects,
◦ The pivotal role of Nrf2: Part 2 - foods, phyto-substances and other
substances that turn on Nrf2,
◦ The pivotal role of Nrf2. Part 3: Part 3 - Is promotion of Nrf2 expression a
viable strategy for human human healthspan and lifespan extension?,
PHYTOSUBSTANCES AND HORMESIS
◦ Plant polyphenols - six epigenetic knockout punches against cancers,
HORMESIS PATHWAYS
◦ HSP70 to the rescue
The Prospects that Emerging Science
Offers Us for Longer Healthy
Lifespans
March 26, 2013
Kopriva Lecture
Montana State University
Presentation by:
Vincent E. Giuliano, Ph.D.
Agingsciences.com