Physiology of aging

1. PHYSIOLOGICAL CHANGES IN AGING IN
CNS
DR UNNIKRISHNAN .P

2. Because of the intimate relation between the
functioning of the nervous system and the
functioning of other body systems, aging of
the central nervous system (CNS) has been
postulated to be a major contributor to aging
of the body as a whole.
MBBS,MD
LONGEVITY
MEDICINE

3. Nothing in this world comprises a negative
element alone
Aging comprises both a positive component of
development [wisdom & experience] along
with the negative component of physiologic
and often cognitive decline

4. Aging is a process of gradual and
spontaneous change resulting first in
maturation and subsequently decline through
middle and late life
Senescence is the process by which the
capacity for growth,function and capacity for
cell division are lost over time, ultimately
leading to death

5. THEORIES OF
AGING
H

6. Tries to prove that there is a “biologic clock”
or “life pacemaker” that confers the unique
longevity of each species
That means an experimental manipulation of
the pacemaker section of the genome should
produce dramatic changes in life span
MBBS,MD
LONGEVITY
MEDICINE

7. For this, an external pacemaker tissue should
coordinate the age related interactions
between tissues and multiple organ systems
Means that neuroendocrine and immune
mechanisms may have a central role in aging
Till now, no objective evidence about such a
pacemaker has been derived ,except for
some early data suggesting the importance of
changes in hypothalamic activity in aging

8. Growth and development represent an
increase in order but aging is characterized as
a breakdown in biologic order and an increase
in randomness
As age increases, genomic errors accumulate
and results in production of defective proteins
which can accelerate the aging process
E.g. advanced glycation end products (AGEs)
predispose to intravascular plaque formation

9. Even though stochastic mechanisms [e.g.
AGE, Telomere shortening] appear @ some
points in age related decline….evidences are
weak to prove the whole theory
“French paradox”
[Rx]
0—0--1

10. decreases in acetylcholine synthesis and
release as well as reduction of muscarinic
receptor plasticity.
??a causal connection between impairment of
central cholinergic function and aging.
A “cholinergic” theory of aging is even more
attractive given the clear role of cholinergic
deficiencies in Alzheimer-type dementia

11. GABA is an important site of drug action for
anesthetic agents and another possible locus
for aging
GABA receptors have decreased specificity to
their agonist molecules in older adults
the demonstration of consistently decreased
anesthetic requirement in older adults also
supports the concept of a link between aging
and altered neurotransmitter dynamics

12. Reactive oxygen species (ROS) or “free
radicals” are routinely produced in the
mitochondria as a byproduct of aerobic
metabolism and oxidative phosphorylation
aging is associated with increased levels of
defective mitochondrial DNA (mtDNA),
presumably because of excessive ROS

13. Lifelong oxidative stress damages cellular
machinery that produces enzymes which do
scavenging of ROS
Hence, ROS, the byproducts of aerobic
metabolism, which is essential for life in all
higher organisms, may generate a “vicious
cycle”

14. calorific restriction  reduce ROS
production and therefore cumulative oxidative
damage decreases  increases life
expectancy
caloric restriction as a therapy prolongs the
life expectancy of laboratory rodents.

15. individuals with an increased demand for oxidative
energy may have a higher “rate of living” that
generates more ROS and reduces life expectancy.
caloric restriction, increases mitochondrial
bioenergetic efficiency and suppress metabolic
stress responses.
Changes in the glucose–fatty acid cycle that occur in
response to near starvation are ?found to be
protective in aging tissues.

17. As of now, the roles of mitochondrial
genetics and oxidative stress in
mechanisms of senescence and death has
been increasingly targeted and the various
theories of aging have begun to coalesce and
unify.

18. CHANGES IN CNS
MORPHOLOGY
WITH AGE
H

19. My brain is lighter [by 7%]; after finishing my
responsibilities …!
widening and deepening of the sulci
decrease in the width of the gyri and an
increase in ventricular size.

20. the meninges thicken
choroid plexus deteriorates
most dramatic in the frontal lobes
reduction in lipids and water content

21. Particularly in the frontal and temporal lobes
Decrease in cortical neurons
Increase in glial cells
Decrease in myelinated axons
phylogenetically younger CNS formations are
affected first
generalized degeneration of axons occurs,
especially in myelinated axons e.g.Spinal
roots

22. .
20%
• mentally healthy
35-38%
• senile dementia
50%
• Alzheimer's disease

23. neurons become irregular
degeneration of axon; especially myelin
sheath
= there is a loss of the coordination of
function by myelinated axons
neurofibrillary tangles
senile plaques
All these changes are more extensive with
dementia

24. • The number of synapses per neuron
decreases
• 95 percent of the receptor surface of cortical
neurons is in the dendrites
• regression of neuronal dendrites reduces
cell-to-cell communication,
• an age-related increase in the number of
terminal branches with end-plates (terminal
sprouting).

25. When a neuron dies, the metabolism and
activity of adjacent neurons increase sharply
as a part of the neural adaptation aging.
These adaptive changes help maintain the
functional capacity of the CNS in the face of
declining neuron numbers

26. a general loss of Nissl substance and
ribosomes
increase in lipofuscin ("wear and tear
pigment," "senility pigment," "chromolipid")
[only constant cytologic change that
correlates with age ]

27. BIOCHEMICAL,
NEUROCHEMICAL,
AND PHYSIOLOGIC
CHANGES
H

28. CBF is reduced in proportion to brain mass
and metabolism and is paralleled by a
reduction in the CMRo2 and CMRGlc
CBF is reduced by 28 percent at age 80, with
more dramatic reductions in patients who
exhibit intellectual deterioration.

29. the normal rise in regional CBF associated
with local neuronal activity is blunted
A loss of autoregulation
CBF show reduced responsiveness to
hypercapnia.
Greater changes in CBF are seen in diseases

30. it appears that cerebrovascular changes may
be the causative agent in reductions of both
CBF & CMRO2, making cerebrovascular
disease a primary force in the aging process.
Indeed, elderly individuals without
cerebrovascular disease appear to have
normal CBF.
3 Long DM: Aging in the nervous system.
Neurosurgery 1985;17:348.

31. CBF is decreased not because of “hardening
of the arteries,” but rather because there is
less brain mass to perfuse [1]
the lower CBF seems to be a consequence of
reduced metabolic demand, not a cause of it
[2]
• [1]Davis SM, Ackerman RH, Correia JA, et al. Cerebral blood
flow and cerebrovascular CO2 reactivity in stroke age normal
controls. Neurology 1983;33(4):391–399.
• [2]Bentourkia M, Bol A, Ivanoiu A, et al. Comparison of
regional cerebral blood fl ow and glucose metabolism in the

32. . decrease in metabolism 
decreasing supply of
energy
slowing of Na outflow of K
inflow
the electrochemical
potential capability of the
nerve cell and its capacity
for prolonged activity are
limited

33. aging reduces calcium movement across
membranes, impairing uptake and elimination
brain may be vulnerable to injury from altered
Ca homeostasis, since many neuronal
processes are Ca-regulated or Ca-facilitated
With the decline in calcium uptake associated
with aging, neurotransmitter release is
inhibited & axoplasmic transport is reduced

34. well described for both beta-adrenergic and
acetylcholine receptors.
Ca++ dependent neurotransmitter release
decrease
an age-related "leakage" of neurotransmitters
[seen with acetylcholine, dopamine, and
glutamate]

35. .
NEURO TRANSMITTER FUNCTION CHANGE
CHOLINERGIC
General decrease
Reduced sympathetic and
parasympathetic ganglia function
DOPAMINERGIC
Reduced anterior pituitary release of
prolactin and luteinizing hormone
Reduced activity in basal ganglia
NOREPINEPHRINE
Reduced gonadotropin
secretion
Reduced sympathetic
function
General decrease
SEROTONIN
General decrease
Decline in cognition and memory
Blunted cardiovascular reflexes
Senescence of estrous cycles
Senile gait, posture, and tremor
Endocrine senescence
Blunted cardiovascular reflexes
Depression
Depression

36. lack of supersensitivity with diminished
stimulation
The activities of GABA) and its synthetic
enzyme glutamic acid decarboxylase are
reduced
In contrast, GABA receptor-binding sites may
be increased.
Leads to an alteration in the response to

37. action potential duration increases
electrical excitability is decreased in general
However, some areas become more
excitable, hence the lowered threshold for
seizure activity seen with a number of
convulsant drugs
the difference between the most and least
excitable structures decreases and CNS
responses to widely different stimuli become

38. weakening of inhibition at the various levels
of its organization
Since inhibitory influences play an important
role in coordinating and integrating CNS
function, this leads to overall changes in reflex
activity and a disorganization of highly
coordinated activities

39. disturbances leading to altered blood
pressure, blood sugar, and acid-base balance
are tolerated less well

40. anterior hypothalamic activity decrease
becomes less responsive to hormonal control.
leads to changes in peripheral organ systems
a decrease in the sensitivity of the
hypothalamic system to the inhibitory action of
various hormones particularly estrogen and
corticosteroids may lead to hypertension,
atherosclerosis, obesity, and diabetes

41. changes in the H-P-A axis lead to reductions in
the ability to respond to external stresses such
as cold, pain, and immobilization.
altered sympathetic and parasympathetic
function [sympathetic activity ↓ed: ↓ed BP &
HR]
altered ability to regular body temperature
during heating and cooling.1

42. The unequal aging process of brain structures
which regulate the CVS and RS leads to altered
cardiovascular and ventilatory responses.
Weakening of nervous control of the CVS
the thresholds for stimulation of the vagus and
sympathetic nerves are raised

43. a reduction in the excitability of the sympathetic
and parasympathetic ganglia
so significant CNS changes are not as
vigorously translated into peripheral changes in
cardiovascular tone
So responses to surgical pain may be blunted
so that hypotension occurs with minimal
anesthesia or in the face of hypovolemia.

44. BEHAVIOURAL &
FUNCTIONAL
CHANGES
H

45. 20 percent increase in reaction time between
20 and 60 years of age
reduced information retrieval.
no decline in the ability to recognize items
The speed and consistency of short-term
memory appear to decline most with age

46. All declines…Intelligence as early as
adolescence.3
neuronal mechanisms involved in neural
plasticity crucial for learning and memory are
retained in the aged but healthy CNS.
the adult brain makes new neurons and this
capability is preserved, albeit at reduced levels,

47. “fluid” intelligence (i.e., the ability to dynamically
evaluate, accommodate and respond to novel
environmental events) deteriorates.
vocabulary, math, and comprehension skills are
reasonably well maintained, as is “crystallized”
intelligence (i.e., accumulated knowledge
Language skills decline after age 70
Emotional problems like depression are

48. Reduced visual sensitivity to short wavelengths
Smaller pupils, slow reactivity
Progressive limitation of upward gaze,
presbyopia
High-frequency hearing loss (presbycusis)
Decreased proprioception and vibration

49. Reduced visual sensitivity to short wavelengths
Ankle jerks decreased or absent, increased
primitive reflexes
Unsteady gait
extrapyramidal dysfunction

50. It is of note that individuals who exercise
regularly have faster reaction times.
A variety of evidence suggests that the decline
in physical activity parallels the decline in
mental activity.3
•

51. dysfunction in the dorsal nucleus of the vagus,
hypothalamus, inter-mediolateral columns of
the spinal cord, and sympathetic ganglia
altered sensivitity of the baroreceptors,
decreases in compliance of the blood vessels
loss of fibers
slowed nerve conduction velocity….LEADS TO
Postural hypotension, (18 percent incidence >
65 years of age)

52. decrease in norepinephrine in the neural
system
decreased receptor responsiveness
axonal degeneration
decreased vasoreceptor sensitivity
decreased adrenergic responsiveness of the
heart.

53. Blood pressure is normally regulated by the
autonomic nervous system through alterations
in vascular tone and myocardial function.
This occurs via sensors in the vasoreceptors of
the great vessels and the carotid sinus, with
neural input to the brainstem through the
glossopharyngeal nerve and carotid sinus
nerves.

54. Also impaired thermoregulation (caused by
impairment of sweating and diminished
vasoconstriction upon cooling)
chronic constipation (disordered bowel motility).

55. A general slowing in the EEG has been
observed.3
older individuals may have predominant
frequencies in the theta range [4 to 7 Hz)],
resembling the slow record of childhood, with
more active individuals having frequencies in
the alpha range (8 to 12 Hz), similar to younger
adults.

56. The generalized EEG slowing is also
associated with the reduced CBF and CMRo2
seen with aging.
focal slowing also occurs, with localized sharp
waves or spikes which are not normally
associated with epileptiform discharges, seen
most commonly in the temporal lobes.3

57. Consistent with decreased proprioception,
somato-sensory evoked potentials are
commonly increased in latency.
Auditory evoked potentials usually are not
altered unless there is high-frequency hearing
loss.
Visual evoked responses usually show a
decline in amplitude of the cortical waves that
may be related to a decrease in attention

58. A reduction in the number of receptor sites and
a decrease in the sensitivity to biogenic amines
(e.g., catecholamines
Decline in cortical neuron density
Decrease in synaptic transmission,NTs &
receptors
Decreased CBF & CMR
PNS: the reduction in the axonal population
and the deterioration of the myelin sheath

59. The MAC decreases with advancing age. To
obtain a rough estimate of MAC in geriatric
patients, the published MAC value of
inhalational agents is decreased by 4[4-6]
percent for every decade of age over 40
years.34
For example, the MAC of halothane in an 80-yr-
old is obtained by multiplying by 84 percent,
which was derived from the formula [100% -
(4% X 4 decades)] times the published
34

60. elderly patients are approximately30%–50%
more sensitive to the effect of propofol
For thiopental sodium and etomidate, the dose
required to reach a uniform EEG endpoint
decreases with age.
relates more to differences in pharmacokinetics.
reduction in the initial distribution volume
higher serum concentrations after a given
dose.

61. An increase in the Vd at steady state has been
shown for TPS increase in the terminal
elimination half-life.
decline in hepatic blood flow in the elderly
decrease in the clearance of etomidate,.

62. The plasma concentration of diazepam required
to achieve a desired pharmacologic effect is lower
in elderly patients (pharmacodynamic response)
prolonged terminal elimination half-life of diazepam
reflects an increased volume of distribution
(pharmacokinetic response).

63. Sensitivity to midazolam is also increased in
elderly patients.
a dose of 0.3 mg/kg was adequate for
anesthetic induction in 100 percent of
unpremedicated elderly patients (age >60 yrs),
whereas 0.5 mg/kg did not adequately induce
anesthesia in 40 percent of young
unpremedicated patients.39
Elimination half-life is longer and total clearance
of midazolam is reduced in elderly versus
40

64. The dose requirement decreases
The dose requirement of fentanyl or alfentanil
decreases 50 percent from age 20 to age 89
have an increased brain sensitivity to these
decrease in plasma clearance and an increase
in terminal elimination half-life also noted

65. there is a greater segmental spread of local
anesthetic in elderly patients undergoing
epidural anesthesia. Serum levels of local
anesthetics are increased
for spinal anesthesia, the time to maximum
spread is shorter and the sensory spinal
blockade is slightly higher in older patients

66. (1) progressive occlusion of the intervertebral
foramina with increasing age so that local
anesthetic solutions injected epidurally have a
greater longitudinal spread
(2) reduced vertebral column height lowering
dose requirements for spinal anesthesia
(3) deterioration of myelin sheaths

67. (4) decreased CNS neuronal population
(5) decreased number of axons in peripheral
nerves, and
(6) alterations in the pharmacokinetics of local
anesthetics in elderly patients.

68. OTHER SYSTEMS
.

69. 20% decrease of skeletal muscle mass
sarcopenia.
But there is no difference in sensitivity of the
elderly to muscle relaxants;
but elimination reduced
So the total dose administered should be
reduced and their effect should be carefully

70. BMR is decreased & is associated with
increased levels of circulating epinephrine
and
diminution of β-receptor sensitivity , resulting
in a decreased ability to cope with physiologic
stressors

71. BMR Reduced lean body mass and TBW, and
increased percentage of body fat alter the
volume of distribution of anesthetic agents.
Altered renal and liver function reduces drug
clearance from the body

72. A 20%–30% reduction in blood volume occurs
by age 75
with TBW, plasma volume and intracellular
water content all decreasing.
So i.v. administration of an anesthetic drug
will be distributed in a reduced blood volume
producing a higher than expected initial
plasma drug concentration.

73. the hepatic metabolism of anesthetic agents
is affected by the reduced hepatic blood flow
hypothermia further prolongs drug action

74. three times more likely to experience adverse
drug reactions.
the risk increases with the number of
medications given.
Much of the information concerning the
pharmacology of anesthetic or any other
agent in the elderly is lacking because the
aged are often methodically excluded from
drug trials

75. Impaired thermogenesis and reduced BMR 
severe postoperative hypothermia and a
protracted recovery
Sweating thresholds remain normal to the
age of ≈70 years; but sweating rate is
reduced
Vasoconstriction in response to cold exposure
is reduced [vasoconstriction is the primary
autonomic response to cold exposure]
the shivering threshold is significantly reduced

76. the sweating threshold is increased
[propofol,alfentanil,isoflurane,and desflurane]
vasoconstriction and shivering thresholds is
reduced[propofol,dexmedetomidine,meperidin
e,and Alfentanil,Desflurane and isoflurane]
clinical doses of all anesthetics markedly
increase the interthreshold range,
substantially impairing thermoregulatory
defenses.

77. postoperative shivering in elderly patients is
relatively rare and of low intensity when it
does occur. metabolic rate increases only
≈20% in the elderly
There thus seems to be little support for the
theory that elderly patients allowed to become
hypothermic subsequently develop
myocardial ischemia because of shivering.

78. Stiff lungs, increased WOB and decreased
force-generating capacity of the respiratory
muscles.
Residual Volume increase with age [5%–10%
per decade]
FRC increase with age [1%–3% per decade]
FEV1 is reduced [6% to 8% per decade]
Closing capacity reaches FRC by the age of
44 when supine and by 66 when upright

79. V/P mismatch
(PaO2) reduces with age
P(A-a)O2 increases
diffusion capacity (DLCO) declines by 2-3
ml/minute/mmHg per decade
response to hypoxia diminishes
decrease in ciliary function and cough is
reduced
Pharyngeal sensation and the motor function

80. Hypertension :attributable to a 50%–75%
increase in arterial stiffness and a 25%
increase in SVR
Increased sympathetic nervous system
activity and decreased peripheral-adrenergic
responsiveness also contribute

81. Ventricular hypertrophy and stiffening limit the
ability of the heart to adjust stroke volume
and impair passive ventricular filling
response to either positive or negative
changes in CVP are typically half those seen
in young

82. fatty infiltration and fibrosis of the heart
increases the incidence of sinus, A-V, and
ventricular conduction defects
decreased myocardial responsiveness to
catecholamines
predisposes to CHF or hypotension
Peripheral neuronal adrenergic loss is
associated with impairment of cardiovascular
reflexes

83. The elderly heart is heavily dependent on an
adequate EDV to maintain stroke volume, and
cardiac filling is in turn dependent on higher
atrial filling pressures because of a stiffened
ventricle and possible diastolic dysfunction.
As a result, the elderly are very sensitive to
hypovolemia.

84. GFR, ↓es from 125 mL/min in a young adult,
to 80 mL/min at 60 years of age, and to about
60 mL/min at 80 years.
But GFR decreases less than renal plasma
flow hyperfiltration  compensates to a
certain extent; but pressure within the
glomerulus increases, possibly accelerating
glomerulosclerosis.
decreases in creatinine clearance, maximum
sodium concentrating ability, and free water

85. Decreases in tubular function, including
impaired ability to handle an acid load, as well
as impaired renin angiotensin and antidiuretic
hormone systems
Decreased thirst response
difficulty in maintaining circulating blood
volume

86. Reductions in renal blood flow and a
diminished response to vasodilatory stimuli
So susceptible to the deleterious effects of
low cardiac output, hypotension,hypovolemia,
and hemorrhage
Anesthetics, surgical stress, pain, sympathetic
stimulation, and renal vasoconstrictive drugs
may all compound subclinical renal
insufficiency.

87. The key to successful
aging is to pay as little
attention to it as possible:
Judith Regan

88. THANK YOU