Good evening. I am just thrilled to welcome
you to our final Longwood seminar of 2016. I'm Gina Vild, I'm
the Associate Dean for Communications and External
Relations at Harvard Medical School. Thank you so much
for being here. I am happy to report to you that
this has been our best attended Longwood seminar series ever. More than 2,200 people
have attended live in this auditorium. And beyond this, the
reach of the seminars has expanded dramatically. Not including this event,
more than 72,000 people viewed from 50 countries
around the world. And even more watch through
our Twitter Periscope stream. And tonight, for
the first time, we are streaming live on Facebook. So to all who are
here in the audience and joining us from
afar, thank you. I hope you'll continue
your relationship with Harvard Medical School. I invite you as
the year progresses to join us on Twitter,
Facebook, and Instagram. And please come
back again next year for our next Mini-Med
School series. Certificates of completion
are available to those who've attended three
or more seminars. This year, we are awarding
500 of these certificates. So I applaud your interest, and
please congratulate yourselves for your attendance. [APPLAUSE] Professional development points
are available for teachers. So if you are here
and would like to receive those professional
development points, please see a member of our staff
and they will take your address and make sure we
get those to you. Within the next couple weeks,
we will be sending you a survey asking for your feedback on the
seminars that you've attended. And I want you to know,
we take this seriously. We refine our program every
year based on the information you provide to us. And we also use it to
select next year's topics. So if you have thoughts
on what we can offer, I invite you to please
take the survey. If you would like
to take one tonight, we have paper
copies in the lobby. I also invite you to view
this year's series, all the past Longwood
Seminar series, and all of the HMs videos on our
video archive on the Longwood Seminar site, or through our
Vimeo or YouTube channels. And before we launch
into the program, I ask that you join me in
recognizing Angela Alberti. Angela, come on up. [APPLAUSE] Angela manages the
Longwood Seminar series. And I know many of you
have come to know her personally and appreciate
her pursuit of excellence in all of the
amazing work she has done on this year's program. So thank you for
expanding our reach and for all of your
wonderful work. Thank you. [APPLAUSE] OK. And on to the program. Tonight's program is The New
Old Age, how the body ages and how to keep it young. Andy Rooney, the wry 60 Minutes
commentator once quipped, "It's paradoxical that the
idea of living a long life appeals to everyone but
the idea of getting old doesn't appeal to anyone." Since the beginning
of time, people have sought ways not just to
live longer but to stay young. From the search for
the mythical fountain of youth to the pursuit
of stem cell research, the quest to stave off the
ravages of aging is relentless. Modern medicine, in many
respects, has delivered. The discovery of antibiotics,
the introduction of vaccines, and other biomedical and
public health measures have ensured that humans
now live longer than at any time in history. And science continues to
make impressive strides. But the anti-aging
industry also has exploded, creating
a $100 billion market for cosmetics
that promise they will turn back the clock. But do they work? Do these miracle
pills and potions really reverse
the aging process? Tonight, we'll find out. Tonight, Harvard researchers
will share with you their insights about the
biological process of aging, what is it exactly,
why does it happen, and what are the
latest discoveries in the science of aging. Please stay for the Q&A. And
you'll have an opportunity to ask your questions. And our scientists will
basically share with you how you can stay
looking younger, feeling and functioning well
for as long as you can. So I'm delighted to
introduce tonight's speakers. Sharon Inouye is a Professor
of Medicine at Harvard Medical School and the director
of the Aging Brain Center at the Institute for
Aging Research at Hebrew Senior Life. Bruce Yankner is a Professor
of Genetics and Neurology and co-director of the
Paul F. Glenn Center for the Biology of Aging
at Harvard Medical School. And our moderator, Amy Wagers,
is the Forst Family Professor of Stem Cell and
Regenerative Biology at Harvard University in the
Harvard Stem Cell Institute. Dr. Wagers's research probes how
changes in stem cell activity affect tissue homeostasis and
repair throughout the lifespan and how these cells
may be harnessed for regenerative medicine. Doctor Wagers has authored
more than 100 primary research and review articles. And her work has been recognized
by an impressive array of awards. So thank you for joining us. And please welcome
tonight's speakers. [APPLAUSE] Thank you very much. I think I have two
microphones here. Thank you very much. And thank you all
for being here today to discuss the new old age. So I thought I would begin by
a general discussion of what is it to age. This is a question that I
pose to undergraduate students in my class every fall. And the answers of
what do you think of when you think about
aging are many and varied. These are some of them. They think about wrinkles,
they think about graying hair. And then more serious
things: organ failure, cancer, stroke, and also wisdom,
knowledge and experience. So you can look at all
of these characteristics, and what you can see is that,
in fact, well, many of these could be considered
to be changes that improve quality of life. Many others actually
are associated with the decline in
physical robustness and an increase in the
likelihood of illness. And so, in a broad
sense, while aging can be looked at as a collection
of physical and behavioral changes that occur as an
individual gets older, in many cases, what
these changes do is to predispose to particular
disorders and dysfunctions. And it turns out, in fact, that
aging is the single biggest risk factor for many chronic
degenerative diseases. This includes diabetes,
dementia, osteoporosis, heart disease, stroke,
cancer, kidney failure, frailty or loss of muscle mass
and function, eye disease, and susceptibility to infection. And these disorders really
represent a growing concern in the medical
community, particularly as the number of
individuals who experience these age-associated disorders
has increased dramatically over the last century. So this plot just plots out
in the United States life expectancy, which
remained fairly flat for many, many years
and has dramatically increased over what is close
to a single generation. About 55% increase in lifespan
since the early 1900s. And this impact in
population aging has been kept at pace also
in other developed nations in addition to the United
States and is emerging even more rapidly in developing nations. And this presents really
a significant and unique challenge for
global populations, both in terms of health
care and in terms of social and economic balance. And so, for example,
population aging has really dramatically changed
the global face of disease in that chronic illness
and cancer are very disproportionately represented
among the older individuals. In addition, as I
mentioned, population aging is changing economics
and social structures, due in part to the larger
health care costs of individuals in the older
generations, and also to a change in the ratio
of elderly individuals in need of care and
younger individuals who are able to provide that care. And so there is
actually, in fact, a growing number of
younger individuals who find themselves
in the challenging situation of caring
for young children and also aging parents. So population aging,
I would argue, is a matter of urgent
and global concern that affects individuals
at all stages of life, not just those individuals
in later stages of life. And when you boil it down, what
the real concern is is that, while we have made dramatic
strides in gains in lifespan, those haven't really
been equivalently matched with improvements
in health span. So what do I mean by this? We all know what lifespan is. It's the number of years in
life or the duration of life. Health span is the number
of healthy years of life, or the duration of
life that's lived without a significant
disease or disability. And so we find ourselves now
in this interesting situation where, as I said, lifespans
are greater than ever before, but the cost of this
longer life seems to be a prolonged period
of chronic disease. And so the goal of
biomedical research into the biology
of aging is really to promote more healthy
aging, and to increase the number of healthy and
productive years of life, and decrease the number
of years spent in disease and disability, as shown here. And now, it's important to
note that achieving this goal does not necessarily mean that
this will result in a longer lifespan. Because while longevity
and aging are linked, it's not necessarily true
that a longer lifespan will lead to slower aging. And in fact, we've
witnessed that to some degree over
the last century. And what we all want
to avoid, of course, is an extension of lifespan
that leads to a trade-off where you have an elongation
or prolongation of disease and disability. So how do we go about
developing therapeutics that target age-related
disease and that promote healthy function
in older individuals? There's, of course,
one obvious strategy, which is to focus on each
of the individual diseases that affect older individuals,
identify distinct mechanisms, and target them individually
via disease-specific mechanisms, as illustrated here. But what if there
was another strategy? What if we could actually
identify common mechanisms that cause predisposition to
age-related diseases and that might be shared
among many or even all of these age-related
dysfunctions? Would we then be able
to develop therapeutics that would have broad benefit
across diseases that typically has been thought of as
distinct, and are certainly treated in that manner? And to do that, I
think it's going to be absolutely essential
to understand aging not just as a loose connection of
physical visible changes, but rather to
understand this process at a deep, cellular, molecular,
and biochemical level. And this is what researchers
into the science of aging are striving to do, using
many different model systems. Because of course, aging is not
a human-specific phenomenon. And this has really
produced what can only be described as
an explosion of knowledge in the area of aging biology. This is a plot that I made
of papers published on aging in the scientific index. And you can see that,
beginning about 15 years ago, there really was this
enormous surge in productivity in terms of research on the
biology of aging and potential mechanisms for intervening
in age-related disease. And this relates, I think,
to two possible causes. First, of course, is the fact
that world population aging is not a phenomenon
that has escaped the notice of scientists in
the scientific community. But more importantly,
and probably driving more of this research, is
the recognition now validated in many different model
systems that, rather than a generalized
process of inexorable wear and tear, aging is
actually a process that is under genetic and
biochemical control, and that its impacts
might be slowed and could, perhaps in
certain circumstances, even be reversed. So what are the mechanisms
that scientists have identified so far that might be
amenable to manipulation in order to promote
more healthy aging? Well, there are many. And I'll say at the outset
that all of these mechanisms interact throughout
the process of aging in a very complex and still
poorly understood fashion. It's clear that
there are changes that occur as a result of damage
to cellular building blocks, to DNA, to protein,
and to lipids. And proteins in particular may
be of particular susceptibility in aging cells. Because it seems that
there's a loss or diminution in the effectiveness of
quality-control mechanisms in cells that control the
proper folding and turnover of proteins as individuals age. It's also clear
that communication between different
organs in your body is crucially important in
maintaining appropriate balance and homeostasis. And this communication network
becomes disrupted with aging. In tissues that regenerate in
response to injury, tissues that recover after injury,
there are often resident stem and progenitor cells. And those cells are lost
or functionally impaired with aging, leading to less
resilience and less robust regeneration and
recovery after damage. There's also a sort of global
experience of an increased inflammatory state,
driven in part by the emergence of a special
or unique population of cells known as senescent cells. These are cells that have
lost the capacity to divide, but nonetheless remain
within the tissues as metabolically active
contributors that send protein signals
to nearby cells that modulate their activity. And these signals tend
to lean towards a more pro-inflammatory state that
suppresses proper tissue function. Metabolism also is critically
important in [INAUDIBLE] with aging. This includes loss of
appropriate nutrient-sensing mechanisms, as
well as disruptions in the ability of
cells to produce energy through dysfunctions in a
sub-cellular organelle known as the mitochondria-- which
normally is the energy powerhouse for the cell--
as well as disruptions in the appropriate
storage of energy. For example, in
the redistribution of fat depots in
aging individuals that leads to a decrease
in insulin sensitivity. And then, at the level
of gene expression, there are instabilities
that arise both in the DNA sequence
itself and in modifications to that DNA sequence
that disrupt the ability of the
chromosomes to maintain appropriate regulation
and that can lead to deleterious
mutations that can disrupt cellular
functions and eventually lead to transformation and cancer. And so, as I said, all of
these mechanisms interact. And very importantly,
all of these mechanisms are found, not just in one
or two or a few cell types, but in many, many,
many different types throughout the body, lending
credence to the notion that there might, in fact, be
underlying mechanisms of aging that are at play in each of
these manifestations of aging as disease that we see with
more prevalence in older populations. And so, in terms of
developing therapeutics, this gives you
hope that you might be able to target these
root causes of aging. But also, very importantly,
because manipulation of the biological mechanisms
of aging that I mentioned in the prior slide have been
in model systems reported to both slow the emergence
of these hallmarks of aging as well as, in some cases,
to restore their more youthful regulation, this
raises the possibility that, for a large number of
existing elderly individuals who are already suffering
with age-related disorders, there might be a path
forward for recovering healthy function. And so what are the
possible mechanisms that have been suggested? Well, the good news is
that at least some of these are easily accessible to
many of us in this audience. Very extensive studies in
many different organisms have clearly demonstrated
the importance of diet in determining the rate of
aging and potentially reversing some age-related dysfunction. And so, in particular, a
low-calorie or even low-protein diet can be useful in
certain situations. Exercise also, very important,
and clearly restores the capacity of
muscle to regenerate. It can also protect from
age-related muscle loss and loss of
dysfunction, improves cardiovascular function as well
as neurogenesis in the brain. And then there are number
of other interventions which have shown benefit in
invertebrate and rodent models but still need to be tested
more fully in higher organisms. So these include interventions
such as reactivation of telomerase, an enzyme
that normally extends the ends of chromosomes to
protect them from damage, which has been shown in
an animal model to improve functioning
and actually reverse degenerative function in
the brain and skeletal muscle in an aging model. Also, activation of
a class of proteins known as sirtuins,
studied by my colleague here at Harvard Medical
School, David Sinclair, who's shown that biochemical hallmarks
of aging in the skeletal muscle and fat can be
reversed by activation of this class of proteins. There's also work from Jan
van Deursen, Jim Kirkland, and Judy Campisi's
groups that indicate that ablation of
those senescent cells that I mentioned that
accumulate with age and can negatively impact cells
surrounding them can actually lead to a restoration of
healthy function in the fat, in the skeletal
muscle, and in the eye. And then finally,
heterochronic parabiosis, an experimental
intervention that documents very
clearly the importance of inter-organ
communication in aging and suggests that rebalancing
this communication mechanism is actually a mechanism for
improving healthy function in a variety of aging tissues. And I want to just say
a couple more words about this particular
intervention because it's a system and
a model in which my lab has done extensive work. So heterochronic
parabiosis is a mechanism by which one can allow for the
exposure of cells and tissues in older animals,
substances that are normally in the blood of younger
animals, and vice versa. And by doing this, one can test
whether there are substances that circulate naturally in
our blood streams that impact the ability of aging cells
and organs to function. And a large number
of investigators have used this model
system to assess the impact of
young-or-old blood factors on the function of aging organs. And I summarized the results
from these studies here. And this is the first
and most exciting observation, is that there are
a number of key characteristics of aging in older animals
that can be restored to a more youthful setting after exposure
to young blood factors. This includes the heart, where
you see a reduction in what's known as cardiac hypertrophy,
or the enlargement of the heart associated with poor function. An improvement in
skeletal muscle repair and a remodeling of
the structure of muscle consistent with better function. An increase in neurogenesis in
the brain and enhanced neural function. Recovery of
remyelinating activity after demyelinating
injury is accelerated. In the pancreas,
insulin-producing beta cells replicate at a higher rate
in old animals exposed to a young blood factor. And there's an enhancement
of bone healing. So these studies
suggest that there may be substances that
are present in youth that are lost from the
blood in old age and that, by supplying
them through young blood, we're able to increase the
regenerative and homeostatic capacity of older tissues. Now interestingly, when
looking at young animals who've been exposed to
old blood, there's a converse effect in some,
but not all, tissues. And so, for instance,
in skeletal muscle, there's a suppression
of regeneration in the brain, a suppression
of neurogenesis, and in the pancreas, a
suppression of beta cell replication in young animal that
have been exposed to old blood factors. But this is not
universal, and there are number of other
characteristics of aging that are not at all impacted
by exposure of young animals to older blood factors. Moreover, there
are some processes such as peripheral
nerve regeneration that become deficient
with age and are agnostic to whether the blood
factors are young or old. And then finally,
it's clear that there are some phenotypes of aging,
some characteristics of aging, that actually are worsened
by exposure of older animals to young blood. So what do we take from
all of these studies? Well, the first
and most important take-home is that the blood
is a very important regulator of the function
of aging tissues. And it serves as a conduit
for sending signals between different organs
in order to coordinate physiologic processes. And this can be manipulated
in an age-dependent manner. These impacts of
blood-circulating factors that vary with age affect
many different tissues that vary quite a bit in
their normal physiology and their regenerative
potential. They can affect tissues
at the level of stem cells as well as existing
cellular architecture. And very importantly,
the responses of particular tissues
to bloodborne factors vary depending on the tissue. And this, to my mind,
means that it's unlikely that simple transfusion
of blood products or blood is going to be effective. Because in that situation,
you can't separate the good from the bad. And so being able to identify
the particular active ingredients in these
systems that are actually responsible for improving
function in older tissues is going to be essential for
developing novel therapies for age-related disease. And relevant to that,
it's, of course, essential to identify
those factors and determine if they're
relevant to humans. And while this work is
still in its infancy, there's just been a
handful of factors that have been identified, and
I think there will be many more. These include both
positively acting factors that seem
to be lost with age and are resupplied
by young blood as well as negatively
acting factors that build up with old age
and can suppress function in younger animals when
provided in older blood. And with respect to relevance
to humans, at least one of these proteins, the
protein GDF11, which we've worked on in the skeletal
muscle, heart, and brain, does seem to be associated
with aging in humans, based on a study out of UCSF
by Peter Ganz's group which showed that individuals who have
high levels of this protein-- or its relative, GDF8--
in their blood circulation have a better outcome
after cardiac events as compared to patients who have
lower levels of this protein, suggesting that there may
be some avenue forward for manipulating levels
of specific proteins in the circulation in order
to promote more healthy aging. And so what I hope you've taken
away from our time together is that there's really very
promising and exciting research in the area of developing
therapeutic strategies for age-related disease. But these have at
their foundation an essential need to understand
the fundamental biology of aging and the basic
pathology of diseases of aging, as these form, really,
the pillars upon which any future therapeutic
would be built. And with that in mind, I want
to just close with a plea, reach out to you to help
support aging research. None of the remarkable
advances we've made in the field of aging
research over the last 20 years would have been possible
without significant support and investment for
biomedical research. And of course, as
many of you will know, the major funder for
biomedical research is the government via the
National Institutes of Health, and for aging
research, the National Institute on Aging-- or NIA. And this plot shows the
annual budget of the NIA. And while this number may look
quite large, if you cost that out per US citizen, you
can actually each year give up one Starbucks coffee
for the amount of money that has been invested
in aging research. One other thing you'll
notice in this plot is that this line is pretty
flat over the last 15 years. And in fact, this is the
first year since 2003 that the NIA has
received a budget that exceeded the rate of inflation. So in real terms,
aging research has lost about 15% support in real
dollars over the last 15 years. And this is already
starting to have an effect. So remember I showed
you this plot showing the increase in
aging-related publications in the scientific literature? Well, 2015 marks the first year
in which that number actually declined. And it's projected that 2016
will show the same thing. And this is not because
the problem is solved. This likely reflects the exit
from the field of researchers and the lower level of
support for those who remain. And so I very much hope
that, through events like this evening's,
we can help people understand the science
of aging and understand the promise of
research in this area so that we can move
forward and provide even greater benefits
to individuals with age-related disease. Thank you very
much for your time. [APPLAUSE] OK, so it is also my pleasure
to announce our next speaker, Sharon Inouye. Sharon Inouye is a Professor
of Medicine at Harvard Medical School, the Milton and
Shirley F. Levy Family Chair in Alzheimer's Disease, and
director of the Aging Brain Center at the Institute for
Aging Research at Hebrew Senior Life. Inouye's research
interests include the epidemiology and
outcomes of delirium, reversible contributors
to cognitive decline, and the relationship of
delirium and dementia. Inouye developed the Confusion
Assessment Model, a method for identification of delirium. She also developed the
Hospital Elder Life Program for delirium
prevention, which is implemented in over 200
hospitals worldwide. She directs the Successful
Aging in Elective Surgery study, a large program project from
the National Institute on Aging exploring innovative risk
factors and long-term outcomes of delirium. Inouye has authored over
220 scientific articles and was elected to the National
Academy Institute of Medicine in 2011. Inouye received the
M. Powell Lawton Award from the Gerontological
Society of America and the A. Clifford Barger Award
for Excellence in Mentoring at HMS. Welcome. Thank you. [APPLAUSE] Can you hear me in the back? OK. So I am really delighted
to be here to talk to you about clinical aspects of aging. I am a geriatrician, and I'll
tell you a little bit more about what that is
in just a moment. So I wanted to start
with what happens to our bodies and
our mind as we age. So with aging, physiologic
changes actually occur in every organ system. So for example, in our heart
we have a decreased ability to generate a high maximum
heart rate with exercise. Our lungs, we lose a little
bit of breathing capacity as we age. Our kidneys have decreased
capacity for clearance. Our muscles have
loss of muscle mass and we become tired or
fatigable more easily. I think many of us are
aware of this phenomenon. I am. There's slower healing
of fractures as we age. The brain has a slower
processing time. You'll be hearing a lot more
about some of the brain changes with aging from Dr.
Yankner in our next talk. The liver has impaired ability
to clear certain drugs. And our immune responses
are diminished. You heard about a
lot of these changes also in Dr. Wager's talk. So what does that
mean for us as we age? Well, under normal circumstances
our body, our organ systems, they have a lot of redundancy,
a lot of extra capacity. And so they can
function very well under normal circumstances. But what happens
is, with stress, we have decreased
physiologic reserve. And what does that mean? That means in the
face of stress, our systems can break down
and be unable to compensate. And that is called
homeo-stenosis, which is a fancy term to mean
that, basically, as we age, things kind of
reach a roadblock. And so those stresses that we
can have problems responding to can be things
like medical illness, like acute illness,
surgery, hospitalization, environmental stressors like
extremes of temperature, for instance, or
social factors like severe psychosocial stress. And so these types of stressors
can tip an older person over if they have decreased
physiologic reserve. So what can you do? I'm going to talk
a lot about what can be done to grapple with
some of these real-life changes on aging. And I want to make
you aware that there is a field of medicine that's
called geriatric medicine. And this includes many
health care professionals. So it includes
nursing, social work, across the span of health
care professionals. But a geriatrician--
and this is what I'm trained in-- is a medical
doctor who has special advanced training and board certification
to meet the unique health care needs of older adults. And so why? Why would you need
that special training? Well, illnesses,
diseases, and medications, they can affect older
adults differently than younger adults. In addition, older adults
often have multiple conditions and multiple medications, and
the care becomes very complex. The other thing is that
there are some illnesses and conditions that
are unique to aging, or they become much more
prevalent as you age. I'm going to talk more about
those in a few minutes. And so in geriatric medicine,
we have a unique focus on prevention. I'm going to talk
a lot about that. So preventing these
things before they occur, maintaining
independence, maintaining functioning in day-to-day
life, and then addressing the special health care
needs of the aging. So who should have
a geriatrician? Well, I would argue
that in the ideal world, just as parents
demand a pediatrician for their children,
ideally, older adults should have a geriatrician. But the reality is there
are not enough geriatricians in the United States to
serve the older population. We only have about a
sixth of what we need. So I would say the
priority for older adults is those who are failing
standard medical approaches, those who have more than two
specialists already involved in their care,
and those who have multiple chronic
complex conditions or complex social and
behavioral management problems. So it's when you are talking
about multiple conditions, multiple complex
management issues, that it would be, I think,
good rather than seeing three or four specialists. Maybe you can continue
with those specialists and also have a geriatrician to
manage and coordinate the care. So now let's talk about some
of the common problems that occur in older adults. I'm only going to talk
about a few of them, but these are ones that are
very common, very prevalent, and that I know many
of us worry about. So falls are one of the
most common problems that affect older adults. One in three older adults 65
and older will fall every year. And the consequence of
this is every 13 seconds, an older adult is seen in
the emergency department in this country for a
fall-related injury. And it's the leading cause of
fatal and non-fatal injuries in the US. And these falls are
extremely costly, both in dollars and in
terms of quality of life. But the good news message
is that many, many falls are preventable. Probably nearly half of
them are preventable. So that means there's
things that we can do to lower our risk for falls. We can do them right now. And we should start
early, I would say, before you get to old age. And so what are some of
those things we can do? Well, balance and
exercise programs have been very well
documented to prevent falls. Tai Chi is a wonderful
activity to help with balance. If you want to find out
about appropriate exercise programs that are available,
you can contact your local Area Agency on Aging for referrals. But also, your physicians
are likely to know what's available. How can you find out
about your risk for falls? Well, there are standard
fall-risk assessments that your health care
professional can do. The other thing that's
very important to know is that there are medications
that increase your risk for falls. And so have your pharmacist
or your physician or your nurse practitioner
review your medications with you regularly, probably
at least once a year, to see if any of the
meds you're on increase your risk for falling. And so things that you
might want to highlight are things like
sedatives, medications for sleep, pain, allergies, or
depression may be risk factors. Not all of them,
but those are just some of the classes of
drugs to make you aware of. You should have your
vision and hearing checked. Yes, your vision
and your hearing are very important
for you to maintain your balance and your posture. So once a year,
get them checked. And then don't do what I
do, not get the glasses that are recommended. So please, please
go ahead and then follow those recommendations. And then, you know,
think about your home. You want to make sure your
home environment is safe. Because most of those falls
that are injurious and serious occur at home, and they
mostly occur in the bathroom. So just to be aware, the
slip and fall in the shower is a classic one. And so you want to
keep your home safe, remove obstacles
in your hallways, make sure your
stairs are well-lit, have grab-bars in your bathroom. These kinds of things can
prevent serious falls. The other thing
is your footwear. You want to have
non-skid footwear that's very well-fitting, including
slippers, to prevent falls. So now, the next big thing
that we all worry about is our brains. And I had the great
privilege of serving on an IOM committee-- that's
the Institute of Medicine. And we just released
this report last year called Cognitive Aging. And it's available free
of charge at this website. And in this
committee, we reviewed all of the literature
on cognitive aging and tried to make
some recommendations. But we had to
start with defining what cognitive aging was. And you wouldn't think that this
would be such a tricky thing. But we actually had
to spend many sessions to figure out what
is cognitive aging. So cognition refers to
those mental functions that help us maintain our
day-to-day functioning in the real-life environment. So what are those things? They're attention, thinking,
understanding, learning, remembering, solving problems,
and making decisions. All the things we need
to do in day-to-day life. And cognitive aging
is the process of gradual ongoing change
that occurs as we age. But it is also highly variable
from person to person, and even within a given
person from day to day. The thing to know is
it's a lifelong process. It begins at birth. So it's not something
that suddenly happens when you reach a certain age. It begins at birth. And it's not a disease
or a level of impairment. Cognitive aging is
happening to all of us. And we'll be hearing more
about the characteristics of it in Dr. Yankner's talk. But I just want to
make a few points. So with aging, cognitive health
is exemplified by our ability to maintain our optimal
cognitive function over time. And so I really want
to stress in my portion of the talk on what we can do to
maintain our cognitive health. But I know you're wondering. I know you're
wondering, OK, what's the difference between cognitive
aging and Alzheimer's disease? Is that a part of the process? Well, it's not. Alzheimer's disease
is a disease, OK? We've used some of those
distinguishing factors for you. So Alzheimer's disease is
a chronic, progressive, neurodegenerative disease,
and cognitive aging, as I just told you, is
a normal part of aging. Alzheimer's disease has
extensive neuronal loss, whereas with normal
cognitive aging, your neuronal
number-- the number of neurons or cells in your
brain-- stays the same, but they may lose their
function somewhat over time. Alzheimer's disease
affects about one in 10 individuals
over the age of 80. Cognitive aging
affects every one, but the extent and nature of
the changes are highly variable. And with Alzheimer's disease,
the declines are progressive and they're severe. But with cognitive aging,
the changes are variable, and they're gradual, and
they don't affect everyone. So what are some of
the key messages? Well, aging affects
every organ system. The brain is one of them. It occurs in everyone. It's a highly dynamic process. It's highly variable. And we're only just beginning
to understand biologically what are the mechanisms,
what's going on, and what are some of the
structural and functional brain changes. You've heard some of
the general changes in aging from Dr. Wagers's talk. You'll be hearing more about
that in Dr. Yankner's talk. One thing to know is that the
neuropsychological domains or those cognitive domains,
they may not change with aging, or some of them do decline, or
some of them actually improve. Things like wisdom and problem
solving actually probably peak in our 70s. So I'm really looking
forward to that. And there are the
other positive messages that actions can be taken to
help maintain cognitive health. So I want to again tell
you, this is not at all, you know, an area to
be hopeless about. And in fact, it's an area
to be very activated about, because we can
make a difference. And in this committee, again,
we reviewed all the literature on interventions that were
effective to try to keep our brains aging healthily. And these were the top
three recommendations that the committee felt
there was adequate evidence to make official strong
recommendations about. And number one, as Dr. Wagers
already stressed is exercise. Physical exercise is actually
the most important thing you can do to maintain
your cognitive health. I just want to underscore
that 10 times for you. So it's cardiovascular exercise,
20 minutes, three to four times a week. That is the number one
best thing that you can do. And you remember, it was
also on the list for falls. So that's a very good thing. It's also on the list
for general aging. So I can't stress enough
how much staying active, having exercise, can benefit
your body and your brain. We don't think about the
benefits for the brain so much, but that is the
number one thing. Reduce your cardiovascular
risk factors. So if it's good for your heart,
it's also good for your brain. So you want to control
your blood pressure. If you have high
blood sugar, you want to get that under control. And you want to stop smoking. These are things that
will benefit your brain. Manage your medications. There's a number of
medications that can affect cognitive functioning. And it's important
that you review them with your physician or
your pharmacist every year. And in fact, Medicare will pay
for a wellness visit for older adults specifically to do this,
to have cognitive assessment and to manage your medications. And so if you don't
take advantage of that, it is a covered benefit. And I just would urge
everyone to please do that. There's some other actions that
can promote cognitive health. You want to be socially
and intellectually active. You want to make sure
you get enough sleep. And if you have
problems with sleeping, seek professional help. And talk to your
health care provider to learn more about
preventing delirium, which I'm going to talk more about now. A variety of external
factors can impact on our pace of cognitive aging. And in this diagram,
I was just trying to show that, while we think
of cognitive aging as being this smooth process, in
reality, what's happening is it's probably a series
of punctuated declines and improvements depending
on what's happening to us. So maybe we're started
on a medication that will temporarily
impair our cognition. Then we improve, and
we get hospitalized, and we decline again,
and we improve. And then we go for major
surgery with an ICU stay, then we really decline. And then it takes us a
long time to improve. And then we're started
on hemodialysis, and we decline, and we never
improve back to our baseline. And so this is often what's
going on for an older person. It's not necessarily
a smooth decline. And so one of those things
that could cause the decline is a condition called
delirium, which is an acute confusional
state that's associated with just
these external factors that I've gone over with you. And the symptoms are that
someone appears very confused in their day-to-day life. They may say things
that don't make sense. They have changes in
their sleep habits. They're very disoriented. They may see or hear things
that are not really there. And they can become either
quiet and withdrawn or stressed and agitated. Those are all
symptoms of delirium. It's a very common problem. And it has serious
complications. It's often unrecognized. Typically, there's multiple
complex things happening. And up to 40% of those
cases are preventable. Through programs like
you've heard about, the Hospital Elder Life Program
that we've created that's up in about 200
hospitals worldwide. And it focuses on these six risk
factors for cognitive decline in the hospital. And we put into
place these kinds of nonpharmacologic
interventions like reality orientation and therapeutic
activities-- that's a fancy word for just
fun activities like word games, current events, trivia
at the bedside-- to keep someone oriented and
engaged, for instance. So what can you do
to reduce your risk? If you know that you're
coming to the hospital or you're going to have a
major surgery, what can you do? Well, here are some strategies. Bring your medication
list, including your over-the-counters, your
herbals, and your prescription drugs so your doctor
knows what you're taking. Bring a medical information
sheet with your allergies, the names of all your physicians
and their contact information, your pharmacy, and any
relevant medical records. Bring your glasses and your
hearing aids and your dentures. I don't know why my patients
always leave those at home. But if you can see
and hear and eat while you're in the hospital,
you're going to do much better. So please bring those with you. Bring familiar
objects from home. You know, things that will
help you stay oriented. Bring books that you like
to read, bring music. And avoid the use of
routine sleeping meds. It just, again,
increases your risk. And instead, use
relaxation approaches. There's a lot of approaches
you can learn online. Music, hand and foot massage. Ask your family to stay
as much as possible. If they can be there to be
your advocate and to help, it makes a big difference. And let your family
and your providers know if you have
any difficulties with confusion or memory. And I've given you our Hospital
Elder Life Program website. If you just Google it,
there's a lot more information there on delirium. And similarly, if
you're a family member, you can do so much to
help your loved one when they're in the hospital. In fact, it's typically
the family member who identifies that
there's been a change. They just say, you
know, my parent, my grandparent is
not themselves. Could you please evaluate? Could you please take a look? I always take that
extremely seriously when I hear that message. Stay as much as
possible, be an advocate, provide comfort,
provide orientation. The ideal environment is quiet
and peaceful with good lighting during the daytime,
but not too bright. Soothing music at
nighttime can really help. The familiar objects. If they do wind up in physical
restraints or bed alarm, ask if those can be removed
as soon as possible. And make sure your loved one
is eating and drinking enough. You want to check with
the doctors that they can. And just to close. So in geriatric
medicine, our goal is to add life to years,
to try to give everyone the maximal quality of
life that they can have, not just years to life. So thank you so much. [APPLAUSE] OK. Thanks very much. So our next speaker
is Bruce Yankner. Bruce is a Professor of
Genetics and Neurology at Harvard Medical School,
director of the Harvard Neurodegeneration
Training Program and co-director of the
Paul F. Glenn Center for the Biology of Aging. His work has contributed
to understanding pathogenic mechanisms
in Alzheimer's disease, down syndrome, and
Parkinson's disease. The Yankner laboratory has
identified a gene network controlled by the
master transcriptional repressor, REST, that promotes
neuronal survival and stress resistance in the aging
brain and may protect against Alzheimer's disease. Dr. Yankner has
received the major award for medical research from the
Metropolitan Life Foundation, the Derek Denny-Brown
Neurological Scholar Award from the American
Neurological Association, the Irving S. Cooper award
from the Mayo Clinic, the Zenith Award from the
Alzheimer's Association, the Ellison Medical
Foundation Senior Scholar Award, and the Nathan W.
Shock Award from the NIA, as well as the Joseph A.
Pignolo Award in Aging Research, and the NIH Director's
Pioneer Award. Welcome, Bruce. [APPLAUSE] Thank you, Amy. We're going to have a test
on that list of awards at the end of the session. So our memories constitute the
only real record of our life: the events, the people,
the places we've been to. And one of the great unanswered
questions in neuroscience is how the brain can store this
vast amount of information, let alone store it
for 70 years or more. And why is it that there
are some people who live into their 90s with a perfectly
good memory whereas others tragically begin to lose it at
a much earlier age and develop Alzheimer's. These used to be basically
academic questions. But now they have central
societal importance because of the
increasing epidemic of Alzheimer's in our society. In this first slide, you
can see the projected cost of Alzheimer's disease,
starting from the present day up until the mid-21st century. About three years
ago, there was a study by the Rand Corporation on
the cost of different diseases in the United States, which
drew the surprising conclusion that dementia, particularly
Alzheimer's disease, might be the most
expensive disorder, exceeding that of cancer
and heart disease. And it was projected
that this cost, which may exceed $1 trillion a
year by 2050 if not brought under control soon, is
likely to contribute to the bankruptcy of Medicare. So this cost was
basically felt to be due to the enormous burden
of getting a demented person through the daily
activities of life, with the constant attention
and care and the loss of productivity
for loved ones who have to spend time
doing that, as well as the absence of any effective
therapeutic intervention or drug at this point. You may be wondering, why,
with the enormous research effort expended in this area,
do we not yet have a drug? And that has not only
perplexed the public, but it perplexes
scientists as well. Are we missing something? My own view is that it
reflects a basic gap in our understanding of the
biology of the aging brain. What you see here are the
brains of three individuals after death: one who died
at 60 of a heart attack, another died at 98 years
old of a heart attack. They were both part of
a cognitive aging study. We know that they did not have
memory loss prior to death. Compared to the brain of
an Alzheimer's disease showed at a higher
magnification. And what is quite
apparent is the shriveling of the Alzheimer brain due to
loss of neurons and connections between neurons. As opposed to the brains of
normal aging individuals, which we now know, due to
a paradigm shift that occurred in the '90s,
do not lose neurons in most parts of
the brain with age. Your brain is very good
at holding onto neurons throughout life, from
birth till death. And given that don't generate
many new neurons during life, that means that most of the
brain cells your born with are the ones you die with. So brain cells must
have been very good stress-resistance mechanism. They have to go through
your teenage years, they have to go through
your kids' teenage years. They have to go through
the 2016 election. So there has to
be a robust system to keep them alive for
70 to 90 years or more. And that is what I'm going to
talk to you about today, how the brain may be the most
resilient organ in the body. And if we understand
it, maybe we could use it for those who are
on the verge of Alzheimer's disease and prevent them from
going over that precipice. So you may ask, if
that's the case, how is it that people lose
memory normally with aging, as Sharon alluded to? Well, this wasn't always
taken for granted. For many years, it was
a controversial issue of neuropsychology whether,
in fact, this even occurred. Because if you look
at the population, it's quite interesting
what you see. This was one of
the first studies to address this by Marilyn
Albert and colleagues in the 1980s. And it showed with formal
neuropsychometric tests, tests of memory,
that individuals show a definable decrement
in short-term recall by the time they
reach middle age, although it doesn't
really affect their activities of
daily life, which becomes more significant in their 70s. But if you illustrate this
data in a different way, shown in the next slide, where
each dot represents the memory of a person
in a memory test, you find that the population
is by no means uniform during aging. The young people
are very tightly clustered in their
memory abilities. But as the population ages,
it becomes more diverse. There are these people who
don't have Alzheimer's disease but who decline considerably
in their short-term memory. But there is another
group that maintains their memory quite assiduously. In fact, they're almost
indistinguishable from the young people. What's more, if you look at
other species, other animals, you see a similar phenomenon. These are rhesus monkeys that
were tested for their memories. They're very tightly clustered
in their young adult years. Towards the end of their life,
they become more diverse. Some show major
cognitive decline. Other monkeys retain
their memory quite well. If you even go down
to the lowly rat, you can see the same
kind of phenomenon. In this index, a higher
number is a worse memory. The young ones are
fairly well-clustered, but the old ones have a
group that are impaired, but many of them
retain their memory. So this is an evolutionarily
conserved feature of the mammalian brain. Then as you go from rats
to monkeys to humans, actually, the proportion
of the population that is impaired with age
is actually increasing. So why is that? So some years
back, my laboratory asked the question
of whether if you looked at the genes
that underlie the aging process or memory, could
you get some insight into these different
groups of individuals, the people who retain
the memory versus people who lost the memory. And one particular
region of the brain that's really key for
this is a small part of the brain-- very tiny, in
fact-- called the hippocampus, shown beautifully here in
this image from Joshua Sanes's lab and Jeff Lichtman's lab. And in the hippocampus,
what happens is sensory and other inputs
flow into this complex network of brain cells. They process it
and they export it to different parts
of the brain, where it's stored until you need it. And then they retrieve
it when you call it back. Something about this breaks
down with age and especially with Alzheimer's disease. And what we found is that, if
you looked at all the genes that are expressed in
these areas of the brain, and you looked at it in people
from 26 to 106 years of age, you saw an interesting pattern. You saw two groups of genes. The ones in red, they are
expressed at very high levels in young people. The ones in blue are
expressed at low levels. And they fall with age. And then there are other
genes that increase with age. And this pattern was
replicated by other groups that looked at other parts
of the brain found with age. Yes, there is a
signature of aging which shows some difference
between brain regions, was pretty conserved from
one region to the next. And for many years,
we didn't understand what this was due to. But with advances in what we
call bioinformatics, big data processing, we were,
in the last five years, able to pinpoint a discrete set
of proteins, shown here, that appear to regulate many of these
changes that occur in the aging brain. And one particular, REST,
had the greatest impact. All these different genes
shown as little ovals were regulated by it. And this was a
surprising finding because this was a
gene that's actually on during fetal
development and was thought to be off in the adult brain. But we found that-- well,
before I get to that, let me just point
out what REST is. REST is a protein that is a
master regulator of genes. So your DNA, your genes, is
a little like the Mass Pike. It's a stream, a long road which
has many different molecules going in different directions
at different speeds with different
functions and goals. And REST is like
the state trooper. It slows the traffic down. It regulates the flow. And it does this by
coordinating the activities of many other proteins that
associate with the genome. And what we found, surprisingly,
is that in young adults-- these are brain cells in what
we call the prefrontal cortex of young adults, an area
that's affected in Alzheimer's. It's very important
for judgment. I'll get to that a little later. And in the aging
brain, this green is the appearance of this REST
protein in the nucleus where the DNA is of older people. It is a dramatic induction. And what is equally striking
is that it's lost at the very earliest stages of Alzheimer's. This is a stage we called mild
cognitive impairment, where people just have very
little memory loss but the process is beginning. And it accelerates as
the disease accelerates. Furthermore, by
analyzing the genes that are controlled by REST,
we found that it controls many genes that are
involved in memory and that have functions
which are directly impacting the ability
of brain cells to survive in the
face of stress. It suppresses genes that will
cause neurons or any cell to die if there's
too much stress. So it keeps cells alive. It repairs DNA
that's been damaged. It regulates genes
that produce energy. And it also impacts genes that
regulate the neurotransmitter communication between
neurons, its network function. And it has a global impact on
adaptive responses in the brain that occur as people age. So this is what we call a
functional MRI scan, which shows the activity
of different brain regions in young
and old people when they're confronted with a task. So many studies have shown--
this is not from our lab but from other labs-- that young
adults, when they're confronted with an executive
task where they have to show organizational
ability, they activate the front of the brain,
which it regulates attention and executive function,
on one side primarily. That part of the brain
goes on, and then it goes off very quickly. In older adults,
starting in middle age, the other side of the
brain starts to chip in and contribute as well. And this increases
significantly as they get older. In multiple tasks,
you can see that here. Young adults, one side. Older adults, both sides. Your other tasks. And it's been shown that this
compensatory response where older people are using
more of their brains is actually helpful, that people
who have impairment in this do worse on these tasks. So this is a positive thing, a
way the brain has of adapting. However, it may explain
certain features or limitations that people perceive
when they get older. Difficulty multitasking,
for instance. If the brain is using more of
itself to do a particular task, it may be more difficult
to do multiple tasks. Plus it's been
shown as people get older, this stays on
longer, whereas in a younger person, after the task
is over, it's done. So you know, if you're
talking to somebody and you're searching
for your car keys, and suddenly your brain
is not switching off from the task of searching for
the keys after you find it, it may be more difficult to
reenter into the conversation. So multitasking maybe
a bit more difficult. However, this
compensatory response may be at the root
of certain changes that are positive that occur in
cognitive function with aging. Many studies have shown judgment
and reasoning improve with age. That's based on experience. It's based on
reduced impulsivity as people get older, which may
have a hormonal contribution as well. Verbal expression continues
to improve into middle age. The size of your vocabulary. You continue to hone
your expression skills as you get older. That's been well documented. Functional math. When you're out to lunch
with a bunch of friends and you need to quickly split
the check or leave a tip, older adults, through experience
or just innate reasoning, do this better
than younger ones. But possibly the most
important is mental health. There is a greater
positive outlook. That may have a
neurobiological explanation. A part of brain called
the amygdala which integrates emotion and memory
is less responsive in older adults to negative stresses,
which may be why it's been shown that people in
their 60s and older tend to brood less
than younger people. Contentment. People accept their
limitations, they use judgment, they have reasonable
expectations, they don't obsess about
things like kids and jobs and so forth as much. That's been well-shown. But interestingly, there was a
study out of Duke and Stanford in 2006, an
often-cited study where they asked 30-year-olds
and 70-year-olds, which group do you think
is more content and happy? And both groups agreed
that the 30-year-olds were. But when they asked
questions that were designed to probe
that degree of contentment and happiness, it was
clear that the 70-year-olds had much better scores. So our perceptions of how
happy or content we are do not always strike true to
the reality of the situation. And this compensatory
response that I'm telling you may also protect some people
from Alzheimer's disease. It's been well
known for many years by neuropathologists that as
much as of quarter of the aging population, when they die,
they have a brain that looks like it has
Alzheimer's in it, based on the proteins
in the brain. However, there was no
evidence that these people had any clinical
decline, any memory loss. And we have found, by
analyzing this group of people that the REST protein,
shown here in green, is markedly increased
in brain cells that have Alzheimer-type
proteins in the people who die with normal memory
compared to the people who die with the same kinds of
proteins, these red proteins, but have developed
Alzheimer's disease. Leading us to suggest
that some people are able to withstand these
toxic proteins that may cause Alzheimer's
disease better than others. And if we could understand
how that happens, we may be able to mimic
it therapeutically. So I'd just like to
close by showing you a video of an experimental
system that we and others are using, the microscopic
worm C. elegans, which is probably the
experimental system that has given us the
greatest insight into the biology of aging. It was used to show the
importance of insulin in metabolic signaling in aging. And we're using it now to
understand brain disease and to try to
develop treatments. Can I have the
video now, please? So these worms, as I
said, are microscopic. You can see them only
under the microscope, but they are
genetically powerful. We can put genes in,
we can take genes out. They live only two weeks, so
you can do lifespan and aging studies very easily. And when you put genes in, you
put a little fluorescent tag on them. And you can then
see exactly where they are, the worms that have
your genes, because they're fluorescent. Now we can also put
disease genes in here. This is a Huntington's
disease worm. It has a gene that causes
Huntington's disease in humans. We also have worms that
have Alzheimer genes. And interestingly, these
worms have a REST-like gene similar to the human gene. And when we activate
that gene, the worms are able to survive
the lesions that they get from the Alzheimer gene. What's more, if we
just take normal worms and we activate this REST gene,
they live longer by about 25%. So you can shut
off the video now. So that's very good
news, at least for worms, and we hope for humans. And it is really our hope
that this kind of approach and others in the
field will speed our search for these treatments
that we so desperately need. Thank you. [APPLAUSE] Thank you very much, Dr.
Yankner and Dr. Inouye. If I could ask you to please
put your name cards up and I'll put mine up as well. So we've received a large
number of questions, and I will apologize
in advance if we're unable to address
everyone's question. I've tried to group them
together so that maybe we can address some
common themes that have emerged in the conversation. And I think the first one,
maybe you both could comment on. There are many
questioners who were interested in the relationship
between the different types of brain pathologies
you discussed: cognitive impairment,
cognitive decline, dementia, delirium, and ultimately
Alzheimer's disease. And I was wondering
if the two of you together might be able
to give some, maybe, perspective and
relationship between those. [INAUDIBLE] Sure. So I'll take the first
part of the question. I'll talk about
delirium and dementia and how they are different. So Alzheimer's disease
is a form of dementia. Dementia is a chronic,
progressive, neurodegenerative disorder. So Alzheimer's disease
and dementia, in the US, we kind of tend to use
those interchangeably because AD, or
Alzheimer's disease, is the most common
form of dementia. Delirium, by contrast, is
an acute confusional state. It tends to be reversible and
not progressive in most cases. And it is, as I
mentioned, usually precipitated by an acute
illness, hospitalization, surgery, and so forth. So it doesn't tend to be the
more chronic progressive. So it tends to be a
transient condition. And do you want to talk more
about cognitive decline? So cognitive decline
during normal aging in the absence of
Alzheimer's disease usually occurs without
the loss of brain cells and is thought to be due
to the loss of connections in that region of the brain, the
hippocampus that I showed you. People who develop what we
call mild cognitive impairment, often thought to be an
antecedent condition to Alzheimer's
disease, in contrast, start to lose their brain cells. And not everybody
with that condition develops Alzheimer's disease. But when it develops into
Alzheimer's disease, what happens is the brain cell
loss becomes more profound. And the protein
lesions, what we call the amyloid and the tangles,
spread out of the hippocampus into other parts of
the brain and start to affect other
cognitive functions. So one of the
great challenges is to understand what is
the basis of the earliest lesions in the
hippocampus and how can we prevent it from spreading out. If we could do that, we might be
able to keep the disease quite mild for quite a long time. Thank you. So a related question
emerges from the fact that we talked about these
dysfunctions emerging in older populations. But in some cases, you might
see them in younger individuals as well. And so the question's
been put forward about cognitive decline
in younger individuals and whether that might
be a distinct disorder or an manifestation
of early aging, similar for Parkinson's disease. Do you want to do it? So there are some what we
call dominant genetic forms of Alzheimer's disease
which aren't common. They account for less
than 1% of the number of cases which can
occur in people as early as in their 40s, for instance. But those mutations
in known genes are quite rare or uncommon. It's much more likely that one
sees early Alzheimer's disease in a person in the
late 50s or early 60s. It's thought now that those
have a likely genetic cause. And there are a
number of genes which have recently,
last several years, been identified as possible
contributors to that. The APOE-4 gene is
one risk factor. So I think it's likely that
many of the very early cases will turn out to have
a genetic component. And that's also likely to be the
case for the very early onset of Parkinson's disease as well. Thank you. Can I add one thing? So there are conditions that
can lead to cognitive decline at younger ages. And these things
can include factors like repeated head trauma,
you know, severe head trauma. I work in the
homeless clinic and I do see a lot of premature
cognitive decline related to accelerated vascular disease. Vascular disease in the
brain can cause dementia. And often,
combinations-- alcoholism can lead to dementia as well,
which can be accelerated. So it's not uncommon that
I see people in their 40s with significant cognitive
impairment related to some of these factors. Thank you. So this question, maybe
Dr. Inouye, you could begin and others may have
other comments. We talked a lot about approaches
that older individuals can take to promote their health. What about preventive measures
that might help aging that you could begin earlier in life? Very early in life, OK. Like your 20s. Well, if you can
plan that far ahead, that's a really good sign of
good executive functioning. I think the
strategies-- and I wish I had started this
earlier-- would be the exercise, healthy diet,
like a Mediterranean diet. Do people know about
a Mediterranean diet? So high in green, leafy
vegetables and high in fiber and low fat, although olive
oil is a very good fat to use if you would
like to do that. And then I think other
things that are probably also important are being engaged
and socially connected. It's been shown that
having social supports and relationships, and really
also having an occupation, something that you can wake up
and be happy to do every day. And that doesn't have
to be a paid occupation. That can be a
volunteer occupation. That can be just something
that you enjoy doing, a hobby. But having something
that is really pleasurable and worthwhile
for you to do every day. I was asked about
meditation during the break. I think meditation is
a wonderful practice to help with maintaining
health in general. And I've just taken
up meditation myself in the last seven months. And I would strongly
recommend it for not only cognition,
but just general health. So I think those are
the factors, the diet, the exercise, observing your
cardiovascular risk factors. I know someone's probably
going to ask about brain games, because that's such a big thing. You know, Lumosity and all that. And I don't know
what the feeling is of my other panelists, but
I think that-- well, there's first of all not been any
scientific evidence that brain games really help you do
anything other than play brain games. But it doesn't
seem to generalize to balancing your checkbook
or the other things that you need to
do in real life. But it's possible that
things may improve. But the thing that I
get concerned about is I hear some of my patients
and even some of my children and my colleagues who
spend a lot of time playing various video
and computer games. And I think the reality is it
takes away time from the things like exercising
and productive work that they should really be
doing, I think, instead. So it's kind of an
opportunity cost. I think it's fine to do those. More than physical
exercise, I don't think they do have the benefit. But I'd love to hear
Bruce, what you think. Well, I agree with you that,
with respect to brain games, the data is still out. Because the randomized
prospective studies, there's one actually
starting now. But a lot of the claims of
the brain game companies are actually not based
on scientific evidence. These studies are not
by any means compelling. So that's not to say
that they don't help. It's just we don't know. Now a friend of mine
once said that he had read that when you exercise,
the amount of additional life you get is equal to the
amount of time you exercise. Now I hotly disputed him
and asked for the reference and he couldn't produce it. I agree with Sharon that
physical exercise is probably the best documented way of
preserving cognitive health. It's been shown in
multiple studies. But I'd like to highlight
another part of the spectrum of life that you should focus
on based on what Sharon said, which comes out of a very
interesting study, the Harvard Study of Adult Development. It's the longest ongoing
study of aging in the world. It started about 75 years ago. It started by taking a group of
sophomores at Harvard in 1942, and then subsequently a group
of underprivileged 19-year-olds from South Boston-- a
group of about 700 people-- and following them
until present. Of the original 750, there are
about 60 people in their 90s still living. And it was quite
a striking study. It had all sorts of people. You know, it spanned
people who were alcoholics, one president of
the United States was included in that group. And the cardinal
take-home message-- this was a study
of men, now-- was that the strength and
positivity of relationships was the single most
important determinant of the quality of aging
among the men as a group, and that the single
most specific factor was how happy men at age 50
were with their marriage as a predictor of how well
they were aging at age 80. I thought that was quite
striking validation of the importance of mental
health in the aging process. I agree. Thank you very much. So maybe we'll move
now to a little bit of discussion of mechanisms. And there was a question about
stem cell function in age. And maybe I'll start
with a couple of comments and perhaps you
would like to share some thoughts from the
perspective of neurogenesis. And so the question was, if stem
cells are failing with aging, why can't we just transplant
more stem cells back in and fix the problem? And one important aspect to
that, at least in the systems that we work with in
my lab-- the skeletal, muscle, and the blood--
is that, as I mentioned, there's this interconnectedness
and interplay between dysfunctions in
different regions of the body. And so it turns out that
in many of these systems, if you simply take
young stem cells and transplant them
into an older organ, they are negatively
impacted by the environment in which they find themselves. And their function is
actually not as robust as it is in a young environment. And conversely, actually,
if you take older stem cells and transplant them
into a younger host, you couldn't actually evoke
a little bit more function from them. And so while loss of stem cells
is a really important aspect of loss of repair, there's
also the suppression of their function
that happens in a sort of cell-extrinsic manner that
has to be taken into account. And ultimately, it may
be that a combination of providing more cells
as well as providing a better soil for them to grow
in is going to be important. I basically agree that
there is a problem now, from the standpoint of
Alzheimer's disease, of putting new stem cells into
the brain if it's going to be exposed
to toxic proteins like the amyloid
and the tangles, which can, in a
cell-extrinsic way-- namely, going from one cell to
another-- harm the cells. But one very promising
avenue is to use genome engineering, which is
just starting to come on board, to change those
stem cells in a way to make them resistant
to that pathology or to help them break
down that pathology. I think that's a very
exciting potential avenue for the future. Thank you. So maybe we could now
move to talk a little bit about clinical tests
and clinical trials. There was a question
about whether there is a reliable test to
predict Alzheimer's disease and sort of separating it
from these other cognitive dysfunctions. So that's a very active area. There are cerebrospinal
and blood tests that can be done, mostly in
the fluid around the spine, to measure the levels of this
amyloid protein [INAUDIBLE] by taking a ratio to
determine how likely it is that a person is progressing
to Alzheimer's disease. But in terms of the
practicality of the situation, it really is probably
at this point no better than a good
neurologist doing very detailed memory testing. So unfortunately, we don't have
any early antecedent biomarkers yet that can reliably
predict Alzheimer's disease. I think the closest we have
now is functional imaging scans and structural
scans that can show early changes in
the hippocampal area that I showed you in
my talk, that that starts to shrink very early on. But for
insurance-related reasons and infrastructure-related
reasons, that's not a kind
of screening test that can be used on the
population at large. So the real push now is to get
a blood test that might tell us 10, 15 years in advance. And that's not a
pie-in-the-sky kind of thing. Because there's
very strong evidence now that Alzheimer's
disease starts years, if not decades, before the
first inkling of any symptoms. So it's not
unreasonable to think that there's going to be
some telltale marker of it very early. Thank you. So this is a really active
area of investigation. There are lots and lots
of people working on this. So we do have good
clues from imaging, from cerebrospinal
fluid, and PET imaging, which is another form of
imaging in addition to the MRI. And trying to correlate
these and find what maybe we can call the Alzheimer
signature that we can recognize, you know, 10 or 15 years
in advance, I think, is what we really
need in order to move the clinical trials ahead. So there are many, many
groups working on this. But it is something
that does take a while. So you raised the
issue of insurance. And another question
related to this is, if such a test is
generated, does that impact on the ability
of individuals who test positive to be insured? And how is the community
thinking about that? Yeah. So that, it's a difficult
issue because I think, at least part of the
Affordable Care Act-- am I allowed to say that? You're allowed to. OK. --was designed to protect people
from this kind of happening, that if something was
found on genetic testing that they could lose
their insurability, lose their life insurance,
lose their health insurance, and so forth. And part of the
Affordable Care Act was really designed to protect
against that from happening. I know in reality,
sometimes those things are hard to enforce. And I know there are ways to be
protected, like you could get tested anonymously if you're
willing to get tested yourself, you know, to pay for it yourself
and not through the insurance, and so forth. But I think, really,
what needs to happen is, if we do
identify a good test, then we really need, as a
society and as clinicians, to really advocate for the
testing to be able to be done, and then to set up the
guidelines of how that would be managed, how it would be
disclosed to patients, to families, what protections
would be in place. And so maybe that's
something you've dealt with in some of your studies. So right now, the importance
of early biomarkers is for clinical trials,
so we could determine what types of drugs
and interventions will prevent the earliest
pathological changes from occurring in the brain. Because we don't yet have a good
drug for Alzheimer's disease. So it's a conundrum in a way. If you had to offer
a person the chance to be tested if they weren't
part of a clinical trial, whether they would want
to know whether this was their fate if there were
no treatment, that's a similar kind of
problem that people with other diseases like
Huntington's disease-- who harbor the Huntington's
disease gene confront, where they can be told
they have this gene but there's nothing
they could do about it. Some people want to know so they
can get their affairs in order. Other people do not. So that's a very
personal decision. And an arrangement
can be made where an insurance company
wouldn't have to know the results of that test. Conceivably, that could
be confidential thing between patient and physician. I think once an
effective treatment for Alzheimer's disease or
an effective intervention is found-- and I'm one of
the more optimistic ones. I think this may occur
within the next five years. The insurance companies will
recognize that, actually, they save money by treating early,
because the cost, as I alluded to in my talk, of treating an
Alzheimer patient it enormous. And the insurance
company would lose more by having a patient progress
at that stage earlier. Now I'd like to actually
echo that last comment. I think this is an issue
that comes up frequently in discussing diseases of aging
and what has, in some settings, been considered the sort of
natural process of aging, and should we really
be intervening in that, and really the cost both to
the patient and to society are great in not providing
the healthiest life possible. And that, I think,
is really what's driving a lot of this
interest in pushing forward medical interventions
in this case. So I think our red
light is blinking. And that means, I think, we've
come to the end of the question and answer session. I want to thank Dr. Yankner
and Dr. Inouye again very much. [APPLAUSE] Thanks all of you, and
have a nice evening. Thank you, Amy. This was fun. Yeah, I love it. Yeah. [INAUDIBLE] Oh, sure. [INAUDIBLE]
