Transcribed

by Kyuun Lee

10/24/14

General Pathology - Pathology Associated w/ Aging by Dr. Sehl

[Slide 2 - Lectures Objectives]
Ok these are the objectives you can read them on your own, there are things that Id
like you to know and these are most likely the things Ill be stressing on the exam
when I make up questions; the idea of differentiating between life expectancy and
life span because were gonna talk about research that mostly addresses life span
and how we wanna extend that if possible and if we are successful at it; Id like you
to at least discuss at a basic level the different theories of aging and well go over
that, I want you to describe the changes that go in a cell at the molecular level as the
individual ages or the cell ages, and how that relates to increasing susceptibility to
disease and hopefully well talk a little about how really the research in the aging
field can have an impact on reducing age-related diseases. Its not so much extending
life span and living those years in diseased states but really to get rid of those or
minimize age-related changes/diseases.

[Slide 3 - What is the relationship]
Im gonna try to throw at you some questions, again I cannot promise Ill be
answering everything to the full extent of your satisfaction because theres really
not a full answer for all of them but we have theories and speculations and some
research which at least supports part of the answer; I want you to start thinking
why most of the diseases occur as we get older especially cancer; 50% of cancers
occur after age 65 and 80% of cancers occur after age of 50. So obviously cancer
happens to be one of those diseases that increases with old age. And I also want you
to start to try to answer the question at least of how age related changes in the cell
or molecular level predispose individuals to disease. Because the cell is really aging
and experiencing the lack of ability to repair itself, thats probably contributing to
the organ becoming diseased and the individual becoming diseased. And then well
be talking about controversial research actually about how we can increase life span
and decrease age related diseases like arthritis, cancer, cardiovascular disease and
diabetes. So I want you to sit back really, try not to take too much notes (lol). Theres
gonna be a lot of specific things Im gonna talk about in resources but thats really
background for you, I just want you to know where its coming from, Im not gonna
hold you responsible for specific molecular changes and specific proteins that are
responsible for certain things because it would take an entire course to understand
that. So I just want to give you a backdrop on aging and how that contributes to the
increase in diseases as we get older. So your focus I would like to be on the patients
youre gonna be seeing in that age group and how these age related diseases are
gonna manifest themselves and how youre gonna treat them. Ok so

Slide 4 - Generally agreed upon:
Let me start by some generalization by what some gerontologists and geriatric
individuals really think, not everybody in that field thinks the same way but the
majority do think aging is not a disease. Most people think we die of old age, just by
deteriorating because were old, its really not a disease. What it does really is its
intertwined with the disease process. So age is very difficult to differentiate what is

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disease and what is normal aging. So it is very important to recognize the two, youll
be able to tell yourself I cant do much about the aging process itself but if its a
disease its possible theres a cure or a way to manage it. So its very important to
differentiate between the two. But they are intertwined and the line is really
crossed. But for sure aging is a major risk factor for most diseases. The longer we
live, the more our chances of getting one or more of those diseases. It is a risk factor
for most diseases, including dental diseases by the way.

Slide 5 - Chart
Alright so lets talk a little bit about those diseases and how their prevalence in the
population. We have heart disease hypertension, stroke, asthma, chronic bronchitis,
any kind of cancer including oral, diabetes and arthritis. All of these have one thing
in common, what do you think? Are they acute diseases? No they are chronic
diseases. That means we really are not gonna be able to cure them. As the patient
gets older the severity of each of these conditions or diseases is gonna get more
severe and we have to manage it. The better we manage it the better the patient is
gonna do functionally. Chronic diseases cannot be cured but they can be managed.
These are the diseases youre gonna encounter with most of your patients. Most of
your elderly patients are gonna come to you with at least one if not 3 or 4 of these
diseases. And you have to differentiate what is causing what and most of the time
theyre gonna be acting at the same time and were gonna talk about syndromes in a
person where its no longer just one disease. And thats why it becomes so
challenging to actually diagnose elderly individuals. Ok and you see some of these
diseases are more prevalent than others, some are more prevalent in women than
men, but in general these are the diseases youre gonna encounter in age 65 and
over patients.

Slide 6 - Leading causes
Again if you look at the leading causes of diseases in the elderly, they really match
more or less the common diseases as well. The diseases of the heart, the
malignancies, the cerebrovascular diseases, respiratory diseases, Alzheimers here,
and diabetes. Ok so more or less the prevalence of the diseases and as well as the
major causes of death in the elderly population really show something in common.

Slide 7 - Biology of aging
Some more questions and these are the ones Im really gonna try to answer to the
best of my ability and to the best of the evidence we have in the literature. Why do
we age, how do we age, can we reverse or slow down the aging process? Can we
extend human life span and remember Im gonna review life span vs expectancy,
and should that be our goal? Should our goal really be increasing the number of
years or increase the life or quality of life in the years we have? And then hopefully
well talk a little bit about the relationship between aging and disease and ultimately
can we prevent age associated diseases. So keep those questions in mind.

Slide 8 - Facts or fiction

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Theres a lot of stories about aging. I mean there are industries that make their
money on the aging process, especially the beauty and cosmetics industry and the
healthfood industry, everything is targeted about how youre gonna prevent or slow
down your aging process. And its so difficult to differentiate facts from fiction.
Because as soon as you see an article like this where red wine can help you live
longer or can reverse some of the diseases you have, the red wine industry picks up
on that and we have people start drinking red wine like crazy. And in order to get
that benefit of the little pigment theyre talking about, you have to drink bottles and
bottles a day to get that benefit. So again people, any kind of thing that comes out
including this ebola business we have, people just take a little piece of it and they go
with it. So its very important because these are the questions patients are gonna ask
you. Even things like moisturizers when they come to you, you tell them oh Im
gonna put a little Vaseline on your lips because theyre dry, they say oh doc do you
know of anything that I can use because really these wrinkles are driving me crazy.
So these are the things you really need to keep up with in both media and scientific
literature and be able to differentiate between what is really hype and what is really
a fact that you can hang your hat on.

Slide 9 - Reasons for Increased Number of Older Adults
Alright lets move on to a little bit of a review so we can all be on the same page. We
definitely have an increase in the elderly population which is great news, and the
reason being theres an increase in life expectancy and decrease in birth rate from
the baby boom phenomenon. We talked about that last year, just a reminder that
13% of our population in the US is 65 and over, so were talking about a large
number here in the 40 millions, and by the year 2030 when most of you I hope are
in the prime of your practices, thats when about 20% of the population 65 and over.
Thats 1 out of every 5 patients at your practice. And unfortunately like I said last
year you can choose not to see pediatric patients and you can send them to pediatric
dentists; unfortunately we do not have a specialty in geriatrics, most of our patients
if they grow up with you theyre gonna trust you and like you and stay with you so
you cant really escape dealing with elderly patients. And you yourself are getting
old. Remember starting today youre gonna grow old with your patients, dentists
are not immune to it you know we still have to get older and recognize our own
deficiencies as we get older.

Slide 10 - Life expectancy
So these are the reasons for increase in number of elderly. Life expectancy we talked
about is the average you expect to live in a particular country. It changes from
country to country. So in the US its now about 79.5, in Japan its over 80, Japan is
really not #1 anymore theres Monaco, Macau I think are inching up on Japan a little
bit, so females still live a little longer than males even though the gap is becoming
narrower. But the life expectancy today a child born is expected to live to almost 80
years of age.

Slide 12 - Graph

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When you look at individuals above 65 today, these numbers are a little old because
I didnt find anything beyond 2004, but really a woman age 65 today is expected to
live up to 20 years. [Im just curious why 85 and 65 are averages?] It doesnt average
because its weighted. We really have more women, but these are probably the
older. The population is a little more women than men, because we live longer. So
these averages are weighted so it doesnt average up. And besides the numbers
probably down here are taken from a different study than the one from 79.5, if you
look at different agencies youre gonna find discrepancies in different numbers.
Curiosity is fine but I dont really expect you to remember this; its approaching 80
lets think of it that way. The average life expectancy in the US is approaching 80, its
not there yet but its higher in women, women are expected to get into their 80s and
lower in men. And the gap is still about 4-5 years. Ok thats all you really need
because those numbers can get really confusing especially if coming from different
sources. Now these numbers are definitely lower, because I am only going up to
2004 here. So any woman aged 65 today, a patient of yours sitting in your chair
today, she has at least 19 to 25 years of living with you. So she has ahead of her
statistically 20 years of dental care from you. Assuming that shes gonna stay in the
same place and you practice in the same area. So whatever you do in the persons
mouth has to last or at least support her for the next 20 years. So this business of I
can patch up this and hopefully thatll last her for the next few years so you really
need to think of most materials/procedures/whatever you put in a patients mouth
may not have a life of 15 to 20 years. Take a composite what is the shelf life or life of
a composite in the mouth? [8 years?] 8 if its done correctly and really perfectly. If
the patient does not smoke or drink and does not stain the margin. If all of that is
under ideal conditions. So that means you may have to remove and replace that
composite a couple of times, 2-3 times. Every time you remove a restoration and do
something to the tooth youre gonna make it a little bit weaker. So if anything you
have to be a little more vigilant in your work and your standards when you work on
an older person ok. So keep that in mind. And another thing is that patient at 65
could be healthier today than she might be at the age of 80 or 85, so you really have
to do as much as you can with the support of course or the desire of the patient
because at 85 you may not be able to have the luxury to do the amount of dentistry
or complexity of the procedure ok. So same thing goes for individuals that are 85 or
over. So dont just look at a patient and say a man is 85 years old, oh hes already
beyond his expiration date. That is not the way to look at people because the older
people make it, the more theyre probably gonna make it because theyre stronger,
theyre gonna survive. Its a natural selection kind of thing. So make sure you make
those years as full of quality as possible because these are probably the most
important ones in that persons life.

Slide 13 - Improvement in life expectancy
And the reason for the improvement in life expectancy we talked about the 2 phases
we talked about the increase in survival of infants, infant mortality has declined, in
the beginning in the 19th and beginning-middle of the 20th century when we had all
of these public health interventions, immunization, improvement in sanitation and
food supply, and the discovery of antibiotics. So infants started to live longer so

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thats the first phase. Then those who made it are also now making it longer in their
middle and later lives because of the advances in medical care and pharmacology,
and people are taking better care of themselves. So taking these two together,
people are living longer so life expectancy is increasing.

Slide 14 - Life span
Now life span on the other hand has not really made much of a difference
throughout human life, and we know that in general we have not really been able to
show that people live under ideal conditions more than 100 to 120 years give or
take. And this is still the best documented person who lived over 120 and she died
in the year 1997 at the age of 122. So we still havent done anything to change life
span but we have done a lot to change life expectancy by making it get closer and
closer to the life span of a human being through the changes in public health issues
and antibiotics and improvements in medical care and people taking care of
themselves better.

Slide 15 - Longevity
Alright so just a couple of more terms Id like you to be aware of in case you come
across them during your reading, longevity is how long a person lives; mean
longevity is the same as life expectancy, maximum longevity is the same as life span
ok so these two and these two are interchangeable.

Slide 16 - Life expectancy vs life span
Again this is the survivorship curve, again demonstrates that life expectancy has
improved and you can see it from the shape of the curve, its going from an S shape
to a rectangular or square shape; but life span has not really improved because all of
these curves are really meeting at the same point. People are just living longer
healthier life but finally succumbing to death at that point.

Slide 17 - Perspectives
Now the two real ways of looking at the aging of humans or organisms because a lot
of times Im gonna talk about non-humans as well; there are two ways of looking at
them, 2 schools of looking at how we age. The evolutionary school and the molecular
biologist school. Evolutionary biologists look at aging as the whole population how
the population ages, and they dont talk about the level of the organism they talk
about the population. And they believe natural selection plays a major role in this.
This is really the most important thing out of this slide, is that evolutionary
biologists believe that natural selection actually culls out the older individuals over
the younger ones because they favor the young for reproduction. Because they feel
like the younger organisms still have the ability to reproduce so nature really loses
interest in the older individuals and focuses on the individuals who are still in a
reproductive age. And aging involves different factors so you really cannot pin it to
just one gene or molecule or event, and its that all of these mechanisms are working
together and thats why its gonna be really difficult to find that fountain of youth.
And thats really fallen out of vogue a little bit.

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Slide 19 - Molecular biologists

And now the focus is really on the molecular biology of aging and studying it on a
molecular and cellular level, and then using that as a transition to the organs and
organism itself. And thats what Im gonna focus on today because thats where all
the research is. Its been very active in the past 10 to 25 years, you see a lot of it if
you actually pick up the NY Times Tuesday science section invariably youre gonna
see something about research in the aging field. They did their research models,
basically on low forms of organisms like yeast, fruit flies, roundworms, mice. Well
talk a little about some of the primates but the major models are really in those
lower forms. They have been able to reverse the process of aging; some molecular
biologists have been able to reverse the process in the laboratory in these
individuals or organisms. Not man, not even other primates. They were able to find
some genes responsible for the aging process that they can manipulate and mutate
to reverse the aging process and shut off some of the proteins responsible for it in
these models, yeast fruitflies roundworms and mice. I just dont want you to get
excited because when people hear it they dont realize that this is still in these
organisms, very low organisms.

Slide 20 - Reasons for Interest
Ok the reason people became interested in the cellular model is because they
realized that there is evidence in the literature that cells grown in culture usually get
older, senesce and get older and when a cell gets senesced it is no longer to replicate
anymore. And the number of replications prior to senescence is directly
proportional to the lifespan of that individual. The longer the lifespan the more
replications that cell is gonna have in the laboratory. If you take a cell and grow it in
culture its gonna replicate up to a point and itll stop, and thats when senescence
occurs. And its really related to the life span of the species. The number of doublings
is inversely related to the age of the donor. The younger the donor the more
doublings, the older the donor the less the number of doublings. And cells taken
from patients with premature aging syndromes like progeria, also have fewer
replications. If you take cells out of a person with progeria youll have less doublings
in those people. Progeria is premature aging. This is actually a 10 year old person
who has aged at a very rapid pace and they die at a young age, but if you look at
their cells they are really older cells and older tissue. If you take cells from an
individual like this the number of replications is gonna be much lower than that
from a normal 10 year old.

Slide 21 - Study of Cellular Aging
The rationale again for focusing on cellular aging is because they figured aging of the
organism has to depend on the aging of its cells or organs. If the cells are aging and
unable to repair themselves and get rid of their waste products, theyre gonna age
and theyre gonna die and thats gonna cause the organ system to age and for the
organism to experience the aging process as well. I just really want you to get the
concept of each slide not go too much in the details of it, if we do that we have to go
into the research and I dont think we have the time for that.

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Slide 22 - Cellular Aging

Cellular aging is basically a progressive alteration in function and form and the
structure of the cell, which leads to a diminished capacity of these cells to repair and
maintain homeostasis. Thats really it. Progressive changes in structure and function
that really lend itself less able to recover from injury and maintain itself and remain
in homeostasis. So older people when they get sick its very hard for them to get back
from an illness. They dont recover really fast they dont bounce back. And the older
the individual is the higher chances are that that illness might be the end of them.
We use the example of pneumonia, when elderly people get it its very hard for them
to recover from it because they dont have the ability to really repair as much as a
younger patient, the ability to bounce back from an insult.

Slide 23 - Functional
Some of the functional changes that youre gonna see in the cells are youre gonna
get, were gonna talk a lot aobut the mitochondria because thats where the energy
of the cell is gonna come from, so if the energy of the mitochondrial function
declines thats when you get a decline in energy production and energy needed to
repair the cell. So oxidative phosphorylation decreases with age, synthesis of a
certain enzyme and proteins decline, capacities for nutrient uptake decline. What is
the best example we can use here? Nutrient decline in old age. What does that
remind you of that we mentioned increases with old age. Come on trying to wake
you up a bit. Umm no, anemia is there is a deficiency in something. If youre talking
about absorption of iron then yeah you could stretch it to that but theres a specific
disease that its increases with old age, its actually the poster disease for dentistry
and systemic disease? Diabetes yeah. This is where the capacity of uptaking glucose
decreases. This is what happens with all these people thats why they become more
susceptible to diabetes because the capacity for them to uptake glucose declines and
when theres damage to the chromosomes younger cells may be able to repair
themselves but older cells and chromosomes cannot repair themselves as well when
theres damage to the chromosome. And when that accumulates you really have an
aging organism.

Slide 24 - Morphologic changes
K now some of the morpho changes, when you look at an aging cell youre gonna see
irregular and lobed nuclei in the cell, youre gonna see mitochondria that is a little
but vacuolated, youre gonna see a decrease in ER and when you think about the
function of ER fatty acid and steroid synthesis youre gonna see that thats gonna
decline, youre gonna see a distorted Golgi apparatus which is gonna affect
glycoprotein synthesis, so you just have to go back and say ok so if this is declining
then what exactly is being affected here and of course accumulation of lipofuscin
pigments, when you see these pigments in the cell that is a telltale of the cell getting
old because that means there is injury to the cell and oxidation products being
secreted into the cell. Ok

Slide 25 - Mechanisms of cellular aging

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Mechanisms of cellular aging, what causes the aging process. From a molecular
point of view there are two things happening and theyre probably happening at the
same time. Theres a genetic clock within the cell that is responsible for the cell
getting older, and theres exogenous influence or external influence on the cell that
is producing free radicals that is damaging the cells. So there is a clock thats being
triggered as well as radicals being produced in the cells, and the cells not really
being able to get rid of these waste products because free radicals are waste
products, and the combination of the two is probably causing the aging of that cell.
So its not really you cant separate one process from the other and Im gonna talk
about each one of them ok. So were gonna talk about the existence of this clock,
were gonna talk about telomere shortening and some of those aging genes that
were found in yeast and worms, were gonna talk a little bit about how oxidative
damage producing those free radicals can progressively accumulate in the cell and
damage that cell ok. And what we can do about it and what science is doing about it.

Slide 26 - Cellular aging
Ok so cellular aging again as a summary is genetic factors and environmental insults
working together to make the cell unable to really repair and maintain homeostasis,
therefore age.

Slide 27 - Aging as a genetic program
So lets talk first about the genetic program. Evidence for that. We already hinted to
that if you take human fibroblasts and put them in culture theyre gonna multiply up
to a point and itll multiply around 50 times, and thats the Hayflick limit. Most of
you took biology and remember Hayflick right. That work was done in the 60s.
When cells taken from children undergo more rounds of replications we talked
about that, we talked about how cells from progeric patients undergo fewer
replications, so there is a fixed number of divisions that cells undergo before they
reach senescence ok.

Slide 29 - Hayflick limit
And this is Hayflick and Moorehead in 1961 they proved the theory that you take
these somatic skin cells, you talk about fibroblasts, now that does not mean every
cell in the body behaves that way there are exceptions. Cancer cells dont work that
way they keep multiplying. Germ cells dont work that way. And any stem cells dont
behave that way ok. And thats why the field of aging when they try to really make
cells multiply and continue to multiply what are you running the risk of at this
point? Cancer. So you have to be very careful about balancing the two because if
youre really gonna have an immortal cell that is a cancerous cell. So you get to a
point where you wanna increase the number of replications but you dont wanna
produce a cancerous cell. So when you look at the literature cancer research and
aging research are very interrelated, especially for those individuals working on
increasing longevity.

Slide 30 - Hayflick limit varies

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We talked about how the replication is really inversely related to the lifespan, and
take a look here mice have a lifespan of 3 years and they undergo 15 cell divisions.
Humans we have a lifespan of 120 years and we go under 50 divisions, the turtle
that lives for 175 years undergoes 110 cell divisions. So that has been shown that
there is an inverse relationship between lifespan and the number of divisions a cell
undergoes before it reaches senescence ok.

Slide 31 - Why does the cell stop dividing?
Alright now lets talk about the telomere functions. Telomeres are those caps at the
end of our chromosomes these are the caps that sit on the chromosomes. The theory
behind how telomeres are responsible for the aging of the cell is that when the DNA
strand starts splitting down, you get one strand with a shorter end the telomere is
being shortened. And as the chromosomes keep on dividing and splitting, this strand
is gonna get shorter and shorter and eventually its gonna stop replicating and that
leads to the Hayflick limit. That is the theory of the telomere shortening ok.

Slide 32 - Telomere shortening appears
Now so again this is the summary that telomeres appear to be the clock we were
talking about, the genetic clock in the cell; the chromosomes keep on splitting, one
strand gets shorter and shorter to the point of not dividing anymore and thats why
you reach the Hayflick limit and senescence.

Slide 33 - Article
Now these are the individuals responsible for the major work that was done on the
telomeres and they did win the Nobel prize in 2009. And they all worked on the
telomere theory and they all worked also on how you can actually reverse that
process by adding a telomerase which is an enzyme that will repair that gap ok so
these are the individuals and if youre interested in their work you can go back and.
So.

Slide 34 - Aging as a genetic program Evidence
And so other researchers in the field also found clock genes in the low form models,
the fruit flies, the roundworms, yeast, and more recently mice, so they did find
certain genes in there that are responsible for the aging process so lets talk about
those.

Slide 35 - Aging gene in mice
In mice they found that there is a gene that makes the protein P-66, that protein P-
66 it triggers the destruction of the cell when the cell gets full of radicals or
oxidative waste. And they believe that this P-66 is part of that aging process so they
did find that there is a genetic component inside a cell that produces certain
proteins or enzymes sometimes that will cause the destruction of the cell. So keep
that in mind for when we talk about reversing the process because well talk about
how that is achieved.

Slide 36 - Aging as accumulated damage

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Ok theres also evidence now we talked about the genes, we talked about the
chromosomes and the telomeres, now were gonna talk a little about how that
external damage or that oxidative destruction and production of free radicals can
damage the cell. Now free radicals damage all the proteins and the lipids and the
DNA in the cells. Some of the diseases that are associated with old age like cataracts
and atherosclerosis and diabetes are caused by glucose actually, hooking up to the
protein or the lipids and forming certain products here where they call them
advanced glycation endproducts (AGE). So when a glucose links to a lipid molecule
or a protein molecule its actually damaging the molecule and making it less
effective. And thats why we are getting an interference in the cross linkage, in the
ability of the cell to really repair itself, and that is really the cause of some of the age-
related diseases ok. So this glycation process is very important to remember. Ok
now another thing that happens the free radical damage, what happens is that
caloric restriction, when organisms are fed a low calorie diet, that means theyre not
producing too much energy, not too much oxidation is going on and not too much
free radicals happening, they tend to live longer. So thats where the diet calorie
restriction diet came about, even for people now they eat fewer calories thinking
they are going to extend their life span and decrease age related change. And were
gonna talk about that when we get to the primates. So caloric restriction lowers the
oxidative damage therefore it tends to increase the lifespan. Again this has been
demonstrated in the low forms such as the yeast, worms, and mice. Variation in
longevity among different species is inversely correlated with the rates of
mitochondrial generation of free radicals. The more mitochondria generates free
radicals, the more active the mitochondria, the more youre gonna have cells
suffering from this inability to repair themselves ok.

Slide 37 - Free Radical
Now free radical oxidative damage is also supported by the fact that when you have
anti oxidants in the system, or catalase, and you add it to the cells of these
organisms like fruit flies, you tend to increase their life span. That means youre
fighting the free radicals. These are anti-oxidants and thats why people take anti-
oxidants. Thats why people eat these foods that are full of them, thats the basis
behind it. These antioxidants are fighting the free radicals thus making the cells a
little bit younger and making them more rejuvenated ok.

Slide 39 - Oxidative damage
Ok now the oxidative damage could come from within the individual or it could
come from outside, and of course if you had for a long time vitamin E, and C, and
some of these superperoxide dismutases are thought to be antioxidants so if you
have low levels of these, its thought that your cells are not gonna be able to fight the
aging process as much and thats why you age at a higher rate. All of these things are
really adding up to the fact that if the body can actually produce its own
antioxidants or if the body is supplemented with antioxidants to fight these free
radicals, we can actually reverse the aging process. And thats been going on in the
lab ok, and thats been translated to all these health food stores and health
industries where everybodys taking antioxidants galore and everybodys eating

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blueberries and things which is fine, these are healthy products and thats fine. I
have no problem resorting to food to manage these things but its only when people
start taking mega-doses of these things when it becomes a little dangerous, because
these things have to go through the liver, the kidney, they have to be processed so it
may not be as benign as you think, especially in those large doses. Ok

Slide 40 - The rate of aging
SO the rate of aging could be related to a balance between what the body is
producing as far as free radicals and products of oxidation, and how much the body
is producing to fight these free radicals. So if youre producing more antioxidants
youll be fighting the aging process, if youre producing more free radicals than
antioxidants your rate of aging will be higher. So its really a simple balance between
the two.

Slide 41 - The role of mitochondria
Now the role of mitochondria is a really major role to play, its the powerhouse of
the cell and where all these free radicals are being produced. The more active the
cell the higher the metabolic rate, the more free radicals and more oxidation going
on.

Slide 42 - Mitochondrial DNA
And they did find that the DNA of the mitochondria is a little bit atypical of the rest
of the DNA in the body, and the mutations happen very frequently and its not very
easily repaired. So when mutations in mitochondrial DNA occur its not as easily
repaired as other DNA in the body. Thats whats responsible for a lot of the age-
related diseases including diabetes and cataracts and things like that. So
mitochondrial DNA does not get repaired as easily, you all know its inherited from
the mother and thats how they track it back, or it could be acquired and so any free
radicals could come endogenously from the person or from the outside
environment, and it does like I said explain a lot of the phenotypes you see in the
aging process.

Slide 43 - Link between mtDNA
And this is a study that was done in 2004 on mice, and they looked at a mouse
without any mutations in mitochondrial DNA, this is a mouse that had a mutation
introduced to the mitochondrial DNA. And so even if theyre the same age this
mouse (mutated) looks much older than this mouse. On that level you can really see
it, its hard to imagine it on a human level ok. But with mice since you know they only
have a lifespan of about 3 years you could very easily do that research. You cant do
that research on men and women. You just cant. Some of it is unethical and some of
it is just impossible due to our life span. So there is definite evidence, there is strong
evidence that when mitochondrial DNA is mutated it produces mice that look older.
So scientists are going to try and see if they can do the opposite and reverse that
process and increase the lifespan of these mice. And thats the next question, can we
do that.

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Slide 45 - 2 Major Research areas

Now theres 2 major research in that area of increasing lifespan in organisms. One
by genetic manipulation they did that with the mice and mutated the mice, the other
is by caloric restriction. Caloric restriction was getting a very nice, strong appeal for
a long period of time until recently when other people started really contradicting
the results. But these are the two areas that are really working together in different
laboratories in different parts of the world where some people are working on
genetic manipulation to increase lifespan of certain organisms and others are
working on caloric restriction, feeding organisms less caloric diet and seeing if they
can reverse the aging process or at least minimize age-related changes. And of
course whenever theres something like that the pharmaceutical industry gets in
there. So they wanna all work on that magic pill to reverse; can we attack it through
genes or mimic caloric restriction by pill because caloric restriction is very difficult
to do.

Slide 46 - Current evidence
So the current evidence is that again human cultured fibroblasts are pushed beyond
the Hayflick limit. This is now the genetic part of the equation, ok. Now we talked
about how the telomeres are the clock and how if we can reverse that process we
can actually reverse that process we can actually extend the life of the chromosome
and the cell. And these are the individuals I showed you who won the Nobel prize,
they found the enzyme telomerase which can actually repair that gap ok, so whats
going on when you have that gap after the strand of DNA splits in half, what happens
is that the enzyme that comes in there repairs that gap but then the telomerase
comes and extends this part of it. So the telomerase is working after that gap has
been repaired by another enzyme. So its not important really for you to know but I
just wanted to let you know that theres another step before the telomerase comes
into play. And the gap is being repaired, that particular strand of DNA now can
replicate more often therefore its gonna have a longer lifespan right. So telomerase
is actually

Slide 48/49 - Diagram
And here it is, it comes into play and it does assist in the repair of that gap after the
splitting of the DNA. And you notice in this graph actually where cell divisions are
actually occurring in the normal cell of the somatic cell so normal cells are gonna
decline decline after they replicate, and when you introduce telomerase theyre
going to reverse that. Cancer cells continue to grow and thats really where the
balance has to come in. How much telomerase do you introduce. Is it possible that
by doing that you are really creating monster cells, cancer cells. Thats why aging
and cancer are two areas that go hand in hand.

Slide 50 - In vitro
So in vitro we know now that inserting genes for telomerase extends the telomeres
by adding DNA bases, its been successful with human fibroblasts in vitro, when you
add telomerase they can actually repair the cells and live longer, replicate more than
50 times. Its been shown in the laboratory. Does it work in vivo? Many many

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questions, there is no answer to that. Is it an effective method of rejuvenating skin?

We dont know. Theyre working on it. Will it create immortal cancer cells? Its likely
yes, and theres a danger of that but we still dont know either. Thats where this
area of research is.

Slide 51 - Current evidence
Now I guess they found longevity genes in certain organisms, and these genes are
really what they call the SIR2 genes, or silent information regulator number 2. Dont
even bother to remember that its not important. I just put it there for those of you
who are interested in reading about it. They found that an introduction of an extra
copy of this SIR2 gene tends to make the yeast live longer. So thats gene
manipulation. Again what it does is it suppresses the production of the waste of
genetic material. So the cell is not being overwhelmed by waste, it does not have to
fight and repair and get rid of all that waste so its living longer. So its like taking care
of your household, its in shape and youre cleaning it and maintaining it and so forth.

Slide 53 - Longevity Gene in mammals
And then they found that in some mammals, this SIR2 gene sometimes it needs help
from this particular molecule (NAD). Again this initial gene is here, adding this
molecule also prevents the production of this waste in the cells and the mice live
longer and it worked in a similar fashion as caloric restriction and were gonna talk
about that. And they found these sirtuin genes in humans as well, but again the
research is really very very preliminary in that area.

Slide 54 - Im not dead yet
This is the INDY genes, single genes when they mutate in fruit flies they found that
when you mutate that gene the fruit flies live a longer life span, from 37 days to 71
days. That may not seem a lot to people but to a fruit fly thats a big number ok. So
going from living 37 days to 71 days is a big deal for a fruit fly. And it increased the
maximum life span by 50%. This is just average lifespan, that means life expectancy
went up. They also increased their lifespan from 70 days to 110 days and thats a
major deal also. And not only did it increase their life expectancy and life span, they
were healthy enough, those fruit flies, so they were out there on the tennis courts
playing tennis you know they were able to multiply and reproduce and do their
thing whatever fruit flies do. Again the model works, theyve been able to
manipulate the genes into inducing a mutation into that specific gene and increase
life expectancy and lifespan and decrease age-related changes ok that is in the fruit
fly, not in us or other higher form organisms.

Slide 55 - Genetic caloric restriction
So what they found what that INDY gene does actually is it regulates the absorption
of protein into the cells and nutrients into the cells, that particular protein. So when
they mutated the gene the nutrients were not able to be taken up by the cells,
therefore the cells were really being starved a little bit. This is similar to caloric
restriction, the cell is getting fewer calories and that is the mechanism for cellular
restriction of calories ok. So it made it more difficult for the fruit flies to use the food

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in their diets, thats why pharmaceutical companies want to discover that pill thats
going to make it difficult for humans to actually utilize the food and nutrients so you
can eat as much as you want but nothings gonna get in there and youll lose weight
or not gain weight. Wouldnt that be wonderful? We arent there yet so dont get
excited yet.

Slide 56 - Current Evidence
Now they also found that genetically engineered mice, they found that if they are
engineered to lack the P-66 protein or the production of P-66 protein, it also
produces mice that can live longer ok. So its all about gene manipulation, take it out
or mutate it or add an extra thing to it but whatever you do here you interfere with
the gene process and put the genetic makeup and again mice were able to live 30%
longer.

Slide 58 - Caloric restriction
And here are our mice. When they are put on a restriction diet, because like I said
these proteins are really interfering with the absorption of nutrients through the
cell membrane, thats why they are living longer. Mice that consumed 40% fewer
calories lived 30-50% longer. So when they subjected the mice to a lower calorie
restriction diet, they found that the mice are living longer as well ok. Now a 40%
fewer calories is a big deal. Lets take a look and say we humans consume about
2000 calories a day. 40% of that is what? 800. That means you have to live on 1200
calories a day to go through what these mice were going through. And thats not
easy thats why you dont see many people going through caloric restriction and
were not even sure if it really works in humans the way its working in lab animals
ok. Alright so.

Slide 59 - Caloric restriction
So, and this is really just describes how caloric restriction works, its through the
sirtuin proteins that are produced and they inhibit some of the protein that increase
metabolic activities, they reduce the death of the cell, and they inhibit the harmful
effects of oxygen. They are known to increase insulin sensitivity and again they are
working to really affect the age related changes.

Slide 60 - Can caloric restriction be mimicked?
And the biggest thing that mimics that caloric restriction they found is the pigment
found in red grapes, resveratrol, and again it became very popular and they have
pills you have to take but again you have to take a tremendous amount of
resveratrol to produce the effect they saw in the laboratory. In the human level its
still not that possible. But its the first time they showed that theres something you
can take to mimic that caloric restriction without eating.

Slide 61 - Monkeys
And then there is a major center in Wisconsin where they are working on now
primates, and this study has been going on for over 25 years, and these are my 2
favorite monkeys Canto and Owen. They are the same age but look at this little guy

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here, hes eating this much compared to this much. And you can see, this guy is
showing more age-related changes than this guy. This guy (left) looks more robust,
he doesnt look as fat either. Caloric restriction according to this group of individuals
in this concept seems to be working for these animals. They predicted that these
animals are gonna live longer on this restricted diet, and theyre gonna show less
age-related disease. So lets see what happened.

Slide 62 - Newspaper article
So in2 007 when they first came out and published it they did say that these
monkeys did live a little bit longer, and those who didnt live longer at least they
didnt show as much sign of aging as quickly or as soon as the others.

Slide 63 - U of Wisconsin
Now this is the Wisconsin, this is the summary o fit, the monkeys are showing many
beneficial signs of caloric restrictions especially significantly less diabetes, cancer,
heart and brain disease, they concluded that caloric restriction slows aging in
primate species. They didnt claim anything about lifespan either, the extension of
lifespan because it was not really significant enough. But this study has critics,

Slide 64 - Recent Study
Another study done at the National Institute on Aging, and in 2012 they published
an article that their finding was that they really contrasted the study from
Wisconsin, they said that the caloric restriction group did not live longer, which the
other one did not claim either; no apparent differences in causes of death, they all
died of the same causes; and cancer, cardiovascular disease, amyloidosis, and
general organism deterioration was presented in both groups so they really refuted
everything the other group said. But thats one study, we really dont have enough,
one cant assume the other means nothing so we need more randomly controlled
trials ok. So the verdict is still out on this caloric restriction business especially in
higher primates, and of course we are one of them.

Slide 66-8 - Effects of Caloric restriction article
Theres also a study that looked at the model here was rats, not mice, and they
looked at what happens when they do caloric restriction and exercise, will that
make a difference on the effect of aging. And they studied the effect by looking at C-
reactive protein, which is an inflammatory factor, and they looked at that and this is
what they found. In young rats usually you have a low level of CRP, low
inflammation, and a high level of antioxidants in their system. Now in the old rats its
just the opposite, more CRP in their system and less antioxidants. Now when they
introduce the 40% caloric restriction, look what happened to the CRP. The CRP the
inflammatory factor went down, and the antioxidants went up. So caloric restriction
seemed to work here in the rats. now were looking at old rats with less of a caloric
restriction only 8% reduction in calories, and they introduced some exercise. And
they found that in this case again the CRP is high, antioxidant is low, and when you
introduce the caloric reduction you reduce the CRP and increase antioxidants, but
when you combine the exercise and the caloric restriction there was an additive

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effect. So yes caloric restriction does work its good not to overeat, its good to
exercise, that makes sense. Im not gonna read it to you, you can do it on your own.

Slide 69 - Normal aging
Now lets move on to people or patients. Lets see how all of this is gonna affect the
way youre gonna treat your patients. Youre looking at healthy aging, and again this
is a review. Healthy aging in people is a progressive decline in each organ system.
Now were no longer looking at the cells because we know that as we age cells do
age, and thats what contributes to the decline in the function of all the organ
systems, and that problem is called homeostenosis. And that means its really
restricting the reserve. The decline should be gradual, linear, it varies from
individual to individual, its varied by the environment, diet, personal habits, in
addition to genes. So we discovered that the aging process in the cell is really
genetic, as well as environmental. So this is really what were saying about humans
based on all the research we know about the cells.

Slide 70 - Age-related functional decline
There is gonna be a decline in muscular strength, the muscle cells, cardiac reserve is
gonna decline, conduction is gonna decline, vital capacity of the lungs, filtration rate
of the kidneys is gonna decline, the elasticity of blood vessels is gonna decline as
well and thats whats gonna give you all of these age related changes.

Slide 71 - Age-related structural
And theres also changes in the composition of the body, theres a decrease in water,
increase in fat, decrease in solids and muscle mass decrease in bone minerals, and
again all of that contributes to diseases we talk about when we get older ok

Slide 72 - Pathologic aging vs healthy aging
These are my two ladies again pathologic aging, when you have all these disease
processes going on it makes the person age faster. So age when you have disease it
also ages you, as well as age being a risk factor for disease. But again it seems the
disease has an upper hand over the aging process. Because this woman is in the 70s,
this woman is in the 90s, and shes aging but its not what we call healthy normal
aging ok.

Syndrome vs Disease

Slide 74 - Diseases
Diseases they tend to attack and stay in organs and they can be treated as such, they
are more common in younger adults and what we base our diagnosis on when we
deal with younger individuals,

Slide 75 - Older adults and diseases
When it comes to older people they have more than one disease usually, they come
in clusters so its hard to differentiate whether its the kidney thats causing this or is
it the liver or a decline in the patients cardiovascular capacity, and these

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interactions of all these diseases we call syndromes because we really cant pinpoint
it. The sum is much bigger than what each disease will contribute to that. And of
course syndromes are more common in older people

Slide 76 - Common diseases
And these are some of the diseases or conditions youre gonna encounter, but youre
also gonna encounter more of the geriatric syndromes ok. And they tend to cross
boundaries so you go from one discipline to the other, so youre gonna see people
seeing more than one physician, they may see a cardiologist and an oncologist and
all of that has to be coordinated by their internist or sometimes if they dont have
one youre becoming their primary care coordinator for all those medications for
that patient. So they do cross disciplines and its important to really work with other
healthcare providers. And they impact mostly on the quality of life, they really it
makes their daily abilities and the ability to go on with daily activities much more
difficult.

Slide 77/8 - Common geriatric syndromes
And these are the common syndromes, falls are a syndrome because it can be
caused by many things, musculoskeletal things or medications a patient is taking or
cardiovascular disease and so forth. Incontinence is a syndrome because its caused
by many different diseases. Dementia, malnutrition also. If you have one or more,
frailty becomes one of the biggest syndromes of them all because it is being caused
by so many different things. And it is really one of the symptoms thats malnutrition.

Slide 79 - Malnutrition diagram
And look how many different things can cause malnutrition. Socioeconomic
conditions, pt not having the money, dementia or depression will cause
malnutrition. Auditory impairment, visual impairment, degenerative diseases, oral
health not having healthy dentition to eat, even vascular disease and some
medications theyre on. Falls, this is another syndrome contributing to another
syndrome. So syndromes are very very difficult to manage which is why they
require a team approach.

Slide 80 - Frailty
Frailty, again is a biological syndrome I just wanted you to be aware of some of the
symptoms and characteristics and when people have 3 or more of these symptoms
they are usually frail,

Slide 81 - How common?
The prevalence of it increases, again you dont have to memorize this but just
recognize, the prevalence increases as pts get older. They seem to be associated
with proteins that are linked to chronic inflammation so all these diseases and
syndromes were talking about, inflammatory factors are very important to
recognize because inflammation in the body seems to be responsible for so many of
these things ok.

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Slide 82 - Frailty
Frailty again may be initiated by disease, lack of activity, inadequate nutritional
intake, physiological changes of aging, and so forth. But it can be prevented and it
can be treated, but it has to be recognized first.

Slide 83 - Flow chart
And this is what they call the frailty cycle, look how complicated it is and how many
things are interrelating for this frailty cycle to occur and how many professionals
would really have to collaborate to treat this patient. You cannot just treat it by just
one or the internist working on the patient ok. You may hve to bring in a physical
therapist to make sure the patient is mobile, a nutritionist to make sure the patient
isnt malnourished, a dentist to make sure the mouth is healthy, all of this, in
geriatric care you must work with other people.

Slide 84 - Frailty
This is another study they did on frailty, I would not get scared by it because its just
one study, they took over 3000 people in their 70s and they asked them to walk for
a quarter of a mile, and those who couldnt make it in 5 minutes they said they were
in a higher risk of dying in the next 4 years, increased risk of having a MI, and risk of
having disability. So its scary but its just one study, the ability to move is really
important. So the older you get you have to stay more active, physically and
mentally. Thats the message I took out of this one.

Slide 85 - The relationship
And basically now the relationship between disease again just to summarize, under
normal circumstances the functional declines that accompany normal aging do not
account for most symptoms. So if the patient is getting older normally without any
disease you should not see any symptoms of disease in that person. Only when an
insult to health occurs the patient cannot bounce back as well and thats when the
aging process really shows itself in people. Because we do have a lot of reserve,
were born with a lot of it and lose it year by year decade by decade, but as long as
we are above that red line or danger level we are managing on a daily basis but
when we get hit by an insult whether its the death of a close person or a medical
condition or even retirement sometimes that has not been planned for, can really
become an insult where the pt shows some of those age related changes ok. But
what aging does is it increases the susceptibility to diseases as a risk factor.

Slide 86 - The importance of aging
And of course Im gonna go back to the question of whether we should extend
lifespan, its not so much really to extend the lifespan but to deal with those diseases
or prevent those diseases related to aging. I think anybody would give up a couple of
years in the nursing home if they could be healthier in the previous 5 years ok so its
very important.

Slide 87 - So historically all the resources have been devoted to separate diseases so
diabetes would get its own money for research and Alzheimers gets its own money,

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I think we need to change that mindset a bit and look at the aging process as a whole
because if we can really prevent or slow down the aging process were gonna
probably gonna prevent or slow down those age related changes.

Slide 88 - In geriatric care
And when it comes to geriatric care keep in mind multiple diseases and syndromes
are really common thats what makes them difficult to treat, syndromes cross
disciplines so youre gonna have to work with other people, communication across
discipline is imperative, and thats why we have interprofessional education now
and we have some of our students working with medical students and nurses at
Bellevue doing exams, and improving quality of life is an ultimate goal. Whenever
you see an older patient you should be asking yourself is this patients quality of life
going to be better or worse after Im done with them. If its gonna be worse dont do
anything unless its just infection and you get rid of that, dont do anything if its
gonna reduce that quality of life. Thats basically what I have for you guys.