medical

1. Aging
Medicine
Changes
Associated
with Aging

2. Aging is an inherently fascinating topic
It has captivated scientists and
philosophers throughout history
For Plato (428–347 bc), those who
lived longer reached a “philosophical
understanding of mortal life” which
led to the desire to understand
everlasting ideas and truths, beyond
the mortal world (Baars 2012)
“For wisdom and
assured true
conviction, a man is
fortunate if he
acquires them even
on the verge of old
age” (Cary, Davis,
and Burges 1852)
Most accurate description of the
general human perception of aging
comes from the Italian poet,
philosopher, and essayist Giacomo
Leopardi (1798–1837)
“Old age is the
supreme evil,
because it deprives
us of all pleasures,
leaving us only the
appetite for them
and it brings with it
all sufferings.
Nevertheless, we
fear death, and we
desire old age”

3. In its broadest sense
Aging broadly
encompasses the general
changes that occur during
an organism’s life span
Though the rate at which
these take place, as well
as the order and mode in
which they occur, varies
widely (Kirkwood 2005)
Such a definition
comprises changes that
are not necessarily
deleterious
Such as wrinkles and
graying hair in humans
Which do not affect the
individual’s viability
(although some might
disagree with such an
assertion)
Anton and coworkers
summarize it as an
equation (1.1) (Anton
et al. 2005)
In which the phenotype is
the end
Result of the interaction
between genotype and
external factors, namely,
diet, lifestyle, and the
surrounding environment
What, then, constitutes aging?

4. Equation (1.1)

5. Changes that may be classified as innocuous must then be differentiated from
those that may lead to an increased risk of disease, disability, or death
A more precise term was coined by biogerontologists, scientists who work
in the subfield of gerontology concerned with the
Biological process of aging
Its evolutionary origins
Potential interventions in
the process: senescence
Senescence is therefore
Progressive deterioration of bodily functions over time
What is aging?

6. Normal human aging has been
associated with a loss of complexity
in multiple physiological processes
and anatomic structures, including
Blood pressure
Stride intervals
Respiratory cycles
Vision
Postural dynamics
All these detrimental consequences
of senescence ultimately lead to
Decreased fertility
Increased risk of
mortality
What is aging?

7. Since the knowledge about aging throughout the years has unexpectedly become increasingly complicated
Initial quest for one overall encompassing theory explaining both the reasons and the intrinsic
mechanisms of aging has given place to numerous processes, which may interact at multiple levels, for
explaining this phenomenon
Relatively young science of aging is now becoming of age, and with it has come the understanding
of some of the underlying biochemical mechanisms at the core of the aging process (Yin and Chen
2005)
Result of advanced analytical studies aimed at the observation and identification
of the “subtle, quiet” age-related changes that occur in living organisms
What is aging?

8. Aim is answering two questions
What is aging?
Why does it occur?
Aging theories

9. Before looking for a cure for aging, it is necessary
to determine whether aging is in fact a disease
Aging is a process _ no matter the cause or mechanism _ that is
characterized by various pathologies, which inevitably lead to death, by
the loss of homeostasis and the accumulation of molecular damage
Disease, on the other hand, is defined as a “disorder or abnormality of
structure and/or function”
Meaning that aging is not a disease, due to the fact that everyone
suffers from it, though disease and aging often overlap
Aging is

10. Process of aging has
been described as
Raging war
between chemical
and biochemical
processes although
a more suitable and
accurate description
might be that of a
complex and rather
interconnected gear
mechanism
On the basis of this
perspective aging is
Outcome of multiple
unwanted chemical
processes
Result in
spontaneous side
products of normal
metabolism
Less active, mutated,
and perhaps toxified
biomolecules such as
Lipids
Proteins
DNA, RNA
Other small
molecules
Aging is

11. There have been multiple
theories as to why most
organisms
The number of theories exceeded 300
and was classified in seven distinct
groups
Many of these theories have since
been discredited or have undergone
modifications and adaptations, while
others have stayed
Broadly speaking, aging has
been ascribed to
Free radical-induced damages
Telomere shortening
Molecular cross-linking
Changes in immunological functions
Senescence genes in the chromosomes
Aging theories

13. Enzymes act as
catalysts to speed
up the biochemical
reactions
It is difficult to slow
them down
Unless mutated or
genetically modified
Side reactions take
place
These result in
build-up of
undesirable side
products
Biomolecules are
thermodynamically
unstable
They become
susceptible to
nonenzymatic
conversion
Can impact orderly
biochemical process
Fundamental reason
at the heart of the
damage-based
theories of aging
There are
reparation
mechanisms
Such mechanisms
are seldom 100%
effective
What does seem to work against biochemistry is chemistry itself

16. There is no clear, undisputed evidence of which changes (molecular,
cellular, or physiological) are the most important drivers of senescence
and/or
how
they
influence
one
another
Consequently, such restricted approaches may thwart the
full appreciation of how different physiological, cellular,
and/or molecular components interact with one another
Each mechanism tends to be, in total or in part,
supported by data
Indicating that they may play a role in the overall
process
Multiple changes take place at numerous levels of the biological hierarchy

17. The goal of an integrative approach will be the compilation of the acquired
knowledge into a single depiction of how the aging process takes place
Ideally capable of characterizing the phenotype at a systemic/organism
level
This goal can only be achieved through a multidisciplinary approach
relying on the overall identification of
Key genes, biochemical pathways, and interactions that are
involved in the aging process
Integrative approach

18. It is also necessary to study
inheritable genetic diseases that
Affect the “speed” of the
aging process
Often resulting in
premature aging
(e.g., Hutchinson–Gilford
syndrome, commonly
referred as progeria)
Physiological experiments
targeted at effectively decreasing
this rate of aging
Such as caloric intake
restriction
Molecular and cellular biology
will be decisive contributors in
unveiling the changes that
organisms undergo during
senescence and the underlying
causes
The multitude of
available data,
especially from high-
throughput studies, will
require a systems
biology approach,
making use of
computational and
mathematical modeling
Integrative approach

19. Between 1/5th and
1/3rd of the total
variation in the adult life
span may be attributed
to genetic variation
Which makes a key
feature for
survival,
particularly at
advanced age
Multiple studies have
focused on the
elucidation of the
genetic basis of
senescence
Looking for
distinct
“signatures” of the
aging process
Many gene-centric
studies have resulted
Identification of
genes whose
expression leads
to significant
alteration in
senescent cells
In spite of the clearly
identified changes in
gene expression, these
studies have so far failed
to unequivocally
demonstrate
If such alterations
are unique and
causal to
senescence or
If they are a
nonspecific
consequence of
reduced or
nonexistent cell
proliferation
Most dramatic age-related changes occur at the molecular level

20. Often carried out
in animal models
May have a limited
contribution to the
elucidation of the
underlying aging
mechanisms in
humans
Senescence
pathways
Are significantly
different among
cells from different
species
Limitation associated with studies

21. Mouse fibroblasts
express telomerase
Display very long
telomeres
In contrast to human
fibroblasts
When cultured,
mouse fibroblasts
undergo senescence
Which takes place
independent of
telomere shortening
Even within the same
species, cells can
exhibit significant
differences in their
senescence pathways
Human fibroblasts
undergo senescence
After a finite number
of divisions
Telomerase expression
has been
demonstrated to
avoid this halt in
proliferation
Difference among species

22. Human mammary epithelial
cells reach a growth arrest
state that is not related to
telomere shortening
They are
mediated by a
tumor
suppressing
protein p16
Importance of p16 in growth
arrest was confirmed by
Immortalization
of these cells by
resorting to
short hairpin
RNA (shRNA),
targeted at p16
Taken as a whole
Data strongly
suggest that
there exist
various
pathways to
senescence
Various pathways to senescence

23. Established and emerging omics strategies and technologies
For a more detailed and comprehensive characterization of the
molecular changes that take place during aging
It will be possible to link these changes to specific cellular and
physiological processes
Improving our understanding of aging
Post-genome era

24. Omics research heavily relies on bioinformatics tools
Such software packages and databases are continuously updated
Meaning that
results should be
constantly
“revisited”
To date, no standard guidelines for “revisiting” are available, as well as no
protocols for their comprehensive reanalysis exist, although some recent
attempts have been carried out
Establishing such procedural rules, guidelines, and protocols and
successfully implementing them could yield potential key discoveries
toward the understanding of relevant biological processes, namely, aging
Post-genome era

26. Occur in all organ systems with aging
Aging is usually accompanied by a decrease in cardiac output and an
increase in blood pressure
Which leads to
arteriosclerosis
Movement impairment is also frequent attributable
to
Degenerative changes that
take place in joints
Combined with the loss of
muscle mass
Physiological changes

27. It was described a positive
correlation between the
hypodermal layer atrophy with age
It should be emphasized that this
was a “regional change”
Commonly affecting the face and
back of hands but not other parts
of the anatomy, such as the waist
Generally held belief that there is a
global neuron loss with age when
In fact, the difference in total
neuron number between the ages
of 20 and 90 is less than 10%
There are some morphological
changes, namely, the significant
decrease of synapses, axon
demyelination, or loss of dendritic
spines
Physiological changes

29. Structural and functional changes produced during specific biological processes, are not
always easily identifiable
What distinguishes pathological from “normal” age-related changes is,
consequently, somewhat fleeting and not clearly defined
The normal, mild changes in neurologic functions that go with aging, and which
do not substantially interfere with everyday activities, unless disease prevails
There are, macroscopic, clearly visible changes in the aging brain, including the
thickening of the arachnoid, the increased ventricular volume, and variable degrees of
white and cortical matter atrophy, that are almost universal
Pathological changes

30. It is also necessary to critically evaluate what may sometimes be
reported as age-related pathological incidences
Positive correlation between hip fracture incidence and age
among postmenopausal women has been reported
This may be a mere
consequence of the
reduced movement
coordination and
visual acuity
observed in older
ages
In other words, these impairments may result in
Higher rate of falls and collisions, which in turn may have resulted in the
reported high frequency of hip (and other) fractures
Pathological changes

32. Considerations pertaining to the psychology of aging inevitably lead to
sociological considerations
Concrete analyses yielding tangible results may be carried out, such as
Evaluating
altered sleep
patterns
Measurements
of cognitive
deficits
Psychological age-related changes are also
intrinsically interlaced with the physiological changes
Individually, as well as collectively, aging members of society
“must learn to age”
Psychological changes

33. Popular culture is youth
oriented
We strive to preserve
our younger self,
resorting to a wide
variety of hyped age-
delaying strategies
Sometimes willing to
undergo surgical
procedures to look
younger and healthy
As a result, older people are
often considered to have
some physical and/or mental
degree of limitation
Stereotypes that the
ever-popular
television does little
to contradict
There are defined and
quantifiable variations that
take place at a psychological
level with aging
Such changes being
observed in the
functional
neuroanatomy
That result in
alterations in speech
production
Psychological changes

35. Those opposed often emphasize the obvious concerns about overpopulation and inequality,
economic collapse due to increasing healthcare needs, and a perhaps “purist” view of
biology, noting that aging is natural and should not be tampered with
On the other side of the spectrum, life extension research advocates underline that
curing aging is not scientifically implausible and that we may soon reach Longevity
escape velocity
Stage of medical
progress at which the
delay in age-related
degeneration
overcomes death to an
extent that allows for
additional research
seeking more effective
therapies later on
There should be little disagreement regarding the need to fight
illnesses, including those that are age-related/caused and
comorbidities
Should we cure aging?

36. It has been known since the 1930s that restricting calories (caloric
restriction [CR]) resulted in life extension in rodents
Also related to CR, it has been shown that modern diets are largely
based on heat-processed foods which may result in
Consumption of
high quantities
of advanced
glycation end-
products (AGEs)
AGEs can affect almost every type of cell in the
organism
Are thought to play a pivotal role in aging and in age-related
illnesses
CR & AGEs

37. AGEs
Proteins and lipids that
covalently bond to sugars
Without the controlling
mechanisms of enzymes
Advanced Glycation End-products

38. It is uncertain whether a low-calorie diet or a reduced intake of
AGEs has a major effect in aging
Animal models suggest that the high levels of AGEs in the
CR-high diet compete with the benefits of CR
Mechanisms of action of these is still
uncertain
CR & AGEs

39. There is the potential for
using pharmacological
agents that act as
Blockers of the cross-linking reactions
leading to AGEs
Blockers of their actions
To fight AGEs and their
potentially deleterious
consequences
Aminoguanidine
Benfotiamine
Metformin
Inhibitors of the reni-angiotensin
system
Aspirin
Pharmacological agents

40. ALT-711 has received much
attention as a next-
generation antiaging agent.
This compound acts by
Catalytically breaking
AGE crosslinks
Has been demonstrated to
have a beneficial effect in
Heart failure
Diabetic nephropathy
Type II diabetes
Age-associated ventricular
and vascular stiffness
There is still the need to
adequately and
exhaustively determine
Potential effects and side
effects of these drugs
ALT-711

41. Initially considered as only harmful to organisms, reactive oxygen species (ROS)
have been recognized to contribute to cellular signaling and homeostasis
These highly reactive chemical species, formed as a natural by-product of the
normal metabolism of oxygen, do exert numerous damaging effects over
lipids, proteins and nucleic acids
These are counteracted by a diverse array of endogenous cellular
antioxidant systems
Whose action may be enhanced by the ingestion of exogenous
antioxidants
Antioxidants

42. The most commonly recognized antioxidants by the general
public are vitamins
A, C, & E
Coenzyme Q10 advertised in beauty creams
Though it has also been described as having a positive
effect in the preservation of mitochondrial respiratory
function in aged rat skeletal and cardiac muscles
Antioxidants

43. Antioxidants do not delay or halt the aging process
They contribute to
increasing
longevity
More worrisome is the increasing commercialization of
dietary supplements containing high concentrations of
these compounds
Some have been
implicated in the
accelerated cancer
development in
mice
Cumulatively, the intake of high-dose
antioxidant supplements
May in fact be more
harmful than good
Due to the fact that
ROS play a role in cell
signal and
homeostasis
At some level, may
have a positive role in
life span
Antioxidants

44. Stem cells therapies have also been heralded as potential treatments of
age-related diseases and rejuvenation
Recently, platelet-rich plasma was used for the recovery of stem cell
senescence in mice
Transplantation of restored stem cells in aged individuals could be
achieved
Which could be applied in the treatment of age-related
diseases
Platelet-rich plasma (PRP)

45. It has been clearly
demonstrated that telomere
extension
Increased cellular
proliferative capacity
in vitro
Positively
contributed to the
reversal of tissue
degeneration in mice
Hyped potential of such
strategies, particularly by the
media
Remaining unproven
This has not barred
pharmaceutical companies from
actively looking for viable age-
prolonging telomerase-based
therapies, such as
TA-65®, a telomerase
activator, already
available
Telomere-based therapies

46. In spite of failing to increase life span, it has positive effects on
Immune
remodeling
Beneficial outcomes over bone, cardiovascular, and
metabolic health
Some precaution is required, as enhanced telomerase
expression has been closely associated with
Cell proliferation Tumor growth
Telomere-based therapies

47. Patients with growth hormone (GH)
and insulin-like growth factor 1 (IGF-
1) deficiencies exhibit signs of early
aging
There are some experimental
data reporting on the benefits
of human GH having beneficial
effects in the elderly
hGH supplements have had a
positive effect over muscle
mass and the strengthening of
the immune system
There have also been reports
detailing the effects of such
supplements over body composition
and metabolism, also resulting in
High blood and intracranial
pressure
Development of diabetes
Hormonal-based therapies

48. Immunosuppressant
rapamycin has been shown
to
Extend maximal life span in
male mice
With limited effects on the
consequences of aging
Rapamycin exhibits serious
side effects, including
Nephrotoxicity
Severe decrease in platelet
numbers
Steep elevation in the levels
of lipids (hyperdyslipidemia)
Rapamycin

49. Another potential
route of intervention
is through the
manipulation of the
klotho gene
This gene codes for
one membrane
protein and one
secreted transcript
Which acts as a
circulating
hormone
Mutations in the
klotho gene have
resulted in
Accelerated aging
in mice
Overexpression of
klotho has been
accompanied by an
Extension in life
span by about 30%
The action
mechanism of this
gene remains unclear
Insulin/IGF-1
signaling pathways
may be involved
More research is
needed to confirm
the role of the
klotho gene in the
aging process
Klotho gene

50. Most futuristic antiaging therapy is that based on the use of
nanotechnology
In spite of the many promises that nanotechnology still holds in a vast
array of applications, the nanotechnology-based biomedical therapies
remain elusive
They entail a level of technological advances that will be a reality in
the near future, but are not yet fully available
There are promising works, such as development of a nanodevice consisting of capped
silica nanoparticles devised to selectively release drugs in aged human cells with an
enormous potential in the treatment of, for example, cancer and Alzheimer’s
Nanotechnology

51. Nanostructures may, in the future, be able to drive chemical reactions that
can ultimately result in the slowing down of the aging process
Or even
completely
revert
senescence
For now the science of antiaging is very much in its
infancy and the road to longevity is still long
The multifactorial nature of the aging process suggests
that
The long searched Fountain of Youth will remain out of our
collective reach for quite some time
Future & now