molecular biology

1. BIOLOGY OF DISEASE
Ageing-Related Disorders
Ng Tze Pin
Gerontolology Research Programme, Department of
Psychological Medicine, Yong Loo Lin School of Medicine,
NUS
NGS GS6882A Biology of Disease (2019)

2. Contextual background
 What is the limit of human life expectancy?
 Biological age versus chronological age?
 Does living longer mean more years spent
in ill health?
 As population age, will there be a
pandemic of disability?
 Can we slow the rate of ageing and
increase life expectancy spent in good
health (healthspan)?
Hot Questions

3. Talking Points
 Biological Ageing
 Global Problems of Ageing
 Frailty
 Dementia
 Successful Ageing

4. Biological ageing
 ‘Physiological’ or ‘functional’ decline with age
 Individual difference in rates of biological aging
 Difference between chronological and
biological age
 Tissues and organs age at different rates
 Average 1% decline per annum
 Respiratory variables most strongly
correlated
 Psychosocial variables most weakly
correlated

5. Biological hallmarks of aging
 Genomic instability
 Telomere attrition
 Mitochondrial dysfunction
 Cellular senescence
 Epigenetic alterations
 Loss of proteostasis
 Deregulated nutrient sensing
 Stem cell exhaustion
 Altered intercellular communication
 Inflammation
(Cell, June 2013)

6. Multisystem physiological
dysregulation may be a key
biological mechanism of
aging
Dysregulation across
multiple physiological
systems increased with age
and significantly predicted
mortality, frailty,
diabetes, heart disease, and
number of chronic diseases
System Biology of Ageing

7. Biological Age
 Traditional biomarkers: visual acuity, skin
inelasticity, blood pressure, FEV1, eGFR,
cognition, glycosylated haemoglobin, pulse
wave velocity, muscle function, etc
 Novel biomarkers: epigenetic/DNA
methylation, proteomic, inflammatory
markers, immune cell markers, telomere
length, etc
Can we measure
biological age apart
from chronological
age?

9. Biological age estimation
Ageing Biomarkers
Males Females
β
Rankin
g
β Ranking
Estimated GFR -0.285 1 -0.245 1
Forced expiratory volume, 1 sec -0.249 2 -0.174 3
Mini mental state examination -0.098 6 -0.213 2
Handgrip strength -0.156 3 -0.077 8
Knee extensive strength -0.127 5 -0.108 6
Timed up and go 0.075 7 0.168 4
Sitting diastolic blood pressure -0.152 4
Haemoglobin -0.068 8
Thigh circumference(cm) -0.120 5
Height (m) -0.101 7
Chair rise time (seconds) 0.065 9
Monocytes (abs x10^9/L) 0.051 10

10. Biological age estimation
The CALERIE Trial
• N=220 non-obese adults
• randomized to 25% caloric restriction or
current diet for 2 years.
• Klemera–Doubal and homeostatic
dysregulation biological age measures
• Calorie restriction slows biological
ageing
Biological age estimators show
responsiveness to the effects of geroscience
interventions

11. Slowing biological ageing
Geroscience interventions with translational potential

12. Talking Points
 Biological Ageing
 Global Problems of Ageing
 Frailty
 Dementia
 Successful Ageing

13.  Increasing life expectancy
 Global population ageing
 Increasing healthcare expenditure and societal
burden
Global Problem of Ageing

14. 1985 1995 1997 2003 2005
Age (Kua) (MCYS) (Yadav) (SLAS) (MCYS)
55+ 4.1% 7.4% 7.8%
75+ 14.4% 26.3%

15. • Known predictors of
mortality, such as
sociodemographic factors,
smoking, and obesity, lose
their importance
• A high disability level, poor
physical and cognitive
performance predict
mortality.
Nybo H, et al, J Am Geriatr Soc 2003; 51:1365–
1373
What best predict
mortality in the oldest
old?

16. BMI and mortality in
older persons
• Body mass index shows a U-shaped relationship with mortality.
• Among older persons aged 65 and above, the overweight-or-obese category of
BMI is not associated with excess all-cause mortality.

17. Talking Points
 Biological Ageing
 Global Problems of Ageing
 Frailty
 Dementia
 Successful Ageing

18. Frailty
• Syndrome of decreased
physiological reserve and
homeostatic dysregulation
• Associated with cumulative
declines across multiple
systems
• Resulting in vulnerability to
adverse outcomes (increased
risk of hospitalization,
dependency in activities of daily
living, institutionalization,
mortality)
(Interventions on Frailty Working Group. J
Am Geriatr Soc 2004; 52: 625–34.)
Physical Frailty
• Weight loss
• Weakness
• Slowness
• Exhaustion
• Inactivity

19. Frailty: Multisystem physiological dysregulation

20. Sarcopenia:
Multisystem physiological dysregulation
Primary physiological dysregulations
• Dysregulated anabolic sex steroid
regulation (testosterone, leptin),
• Energy metabolism (via sex
steroids and insulin–leptin dual
signaling)
• tissue hypoxemia (hemoglobin, red
cell count)
Secondary mediatory involvement
• myocyte‐ and adipocyte‐derived
cytokines, HPA stress hormones
(cortisol, DHEAS), glomerular
function, and immune cell
regulatory and inflammatory
cytokines and glycoproteins.

21. Frailty and Immuno-senescence
Frailty is associated with markers of
senescence in immune cell popuations
• α/β T cells
• CD3+,
• CD45RA+,
• central memory CD4 cells
• Loss of CD28 expression, especially in
CD8+ T cells
• γ/δ T cells
• CD27,
• IFNγ+TNFα- secretion by γ/δ2+ cells
• IFNγ-TNFα+ secretion by γ/ δ2- cells.
• B cells
• More exhausted B cells
• CD38+ B cells
• APC (dendritic cells)
• CD14+CD16+ inflammatory
monocytes
B SE p
Association of frailty with:

22. Pathogen Load and Frailty
A high pathogen load of latent
infections is associated with
increased risks of frailty and
mortality
Pathogenic Load Adjusted
3-6 7-9 P OR/HR (95%CI) p
Frailty Index 0.240 ± 0.074 0.286 ± 0.095 0.001 0.035 (0.007, 0.063) 0.015
Robust (0) 40.7 (33) 19.7 (12) 1
Pre-frail (1-2) 53.1 (43) 55.7 (34) 1.86 (0.77, 4.49) 0.166
Frail (3-5) 6.2 (5) 24.6 (15) 0.001 8.54 (2.32, 31.5) 0.001
Deaths 62.5 (50) 81.7 (49) 0.014 1.53 (1.01, 2.31) 0.046
% (N) or Mean±SD
¶ Adjusted for sex, age, education, smoking and alcohol history

23. Frailty and Inflammation
Correlation with Frailty Index
Cytokines/ Chemokines β p
sgp130 (ng/ml) 0.372 <0.001
I-309 aka CCL1 (pg/ml) 0.266 0.010
MCP-1 aka CCL2 (pg/ml) -0.345 0.001
RANTES aka CCL5 (pg/ml) 0.251 0.013
BCA-1 aka CXCL13 or BCL (pg/ml) 0.361 <0.001
Leptin (ng/ml) 0.233 0.015
Frailty is associated
with levels of
circulating immune
markers of
inflammation

24. J Am Med Dir Assoc.2014 Sep;15(9):635-42.
Socio-economicFactors
Robust
n=883
Pre-frail
N=712
Frail
N=90
P
value
Age 75+ % 7.9 20.2 36.7 <0.001
Female % 64.1 64.2 67.8 0.66
No formal education % 15.1 26.1 34.4 <0.001
1-2 room public housing % 16.7 25.6 41.1 <0.001
Non-Chinese ethnicity % 9.0 12.6 14.4 0.010
Single, divorced, widowed % 29.0 39.3 52.2 <0.001
Living alone % 12.9 18.7 26.7 <0.001
Current smoking % 19.7 25.5 27.3 0.004
Daily alcohol drinking % 3.4 2.4 1.1 0.114
Chronicdiseases
Robust
n=883
Pre-frail
N=712
Frail
N=90
Pvalue
Cardiovascular disease % 5.7 10.5 15.6 <0.001
Hypertension % 58.1 63.8 80.0 <0.001
Diabetes % 17.1 23.9 31.1 <0.001
Stroke % 1.6 4.1 12.2 <0.001
Coronary heart disease % 3.2 4.5 7.8 0.028
Atrial Fibrillation % 2.2 4.4 4.4 0.016
Heart failure % 0.7 2.3 3.3 0.003
Cataracts/ glaucoma % 26.3 32.9 51.1 <0.001
Asthma/ COPD % 3.2 6.2 11.1 <0.001
Arthritis % 13.5 15.7 20.0 0.063
Osteoporosis % 4.6 6.7 12.2 0.003
Gastrointestinal problems % 5.9 7.9 15.6 0.002
Chronic Kidney disease % 4.5 10.8 18.9 <0.001
Cancer % 2.6 2.3 6.7 0.29
Thyroid disease % 4.6 5.8 1.1 0.86
Clinical Factors
Robust
n=883
Pre-frail
N=712
Frail
N=90 P
Poly-pharmacy (>5 drugs) % 10.0 20.1 28.9 <0.001
Poor self-rated health % 0.3 1.3 6.7 <0.001
Visual impairment % 20.7 31.7 45.6 <0.001
Hearing impairment % 1.7 4.1 3.3 0.012
FEV1/ FVC<0.7 % 15.5 21.8 31.1 <0.001
Nutritional Status Factors
Robust
n=883
Pre-frail
N=712
Frail
N=90 P
Obesity (BMI ≥ 30) 5.1 7.4 13.3 0.002
High nutritional risk (NNS score≥3) 21.9 37.5 53.3 <0.001
Low albumin (<40 g/ L) 8.8 13.2 18.9 <0.001
Low haemoglobin 34.9 41.0 47.8 0.002
Low total cholesterol 0~5.19mmol/ L) 47.0 52.3 55.1 0.022
Is common and presents a
diversely negative social and
clinical profile
Physical Frailty
• Weight loss
• Weakness
• Slowness
• Exhaustion
• Inactivity

25. Physical Frailty
J Am Med Dir Assoc.2014 Sep;15(9):635-42.
• Weight loss
• Weakness
• Slowness
• Exhaustion
• Inactivity
Strongly predicts
Incident ADL
disability,
hospitalization, poor
quality of life and
mortality

26. Physical Frailty
Physical frailty predicts increased risk
of incident depression
Physical frailty is associated with
higher prevalence of cognitive
impairment and predicts increased
risk of incident cognitive impairment
Frail elderly with concurrent cognitive
impairment are at highest risk of
developing neurocognitive disorder
(MCI-Dementia)
Relative Risk were adjusted for age, gender, education, medical
comorbidity, current smoking, alcohol drinking, APOE4 carrying status,
depressive symptoms
0
1
2
3
4
5
6
7
8
Prevalent Cognitive
Impairment
Incident Cognitive
Impairment
Robust Pre-frail Frail
Hazard Ratio
Relative Risk were adjusted for age, gender, education, medical
comorbidity, current smoking, alcohol drinking, APOE4 carrying
status, depressive symptoms
0
0.5
1
1.5
2
2.5
3
3.5
Depression (GDS>=5)
Robust
Pre-frail
Frail
Relative Risk
Relative Risk were adjusted for age, gender, education, medical
comorbidity, current smoking, alcohol drinking, APOE4 carrying status,
depressive symptoms
0
1
2
3
4
5
6
7
No Cognitive Impairment Cognitive Impairment
Robust Pre-frail Frail
HR of Incident NCD (MCI-Dementia)
J Am Med Dir Assoc. 2014 Jan;15(1):76.e7-76.e12
J Geron Med Sc Biol Sc 2016 (in press)

27. Frailty Is Reversible
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0M 3M 6M 12M
Fraily
Score
Change
from
Baseline Nutrition
Cognition
Physical
Combination
Control
Frailty
-1
-0.5
0
0.5
1
1.5
2
2.5
3
0M 3M 6M 12M
Knee
strength,
kg
change
from
baseline
Nutrition
Cognition
Physical
Combination
Control
Strength
Am J Med. 2015 Nov;128(11):1225-1236.

28. COMMUNITY-BASED AND CLINIC-SUPPORTED
INTEGRATED MULTI-SECTOR SERVICE MODEL
Community screening:
- Frailty Screening (‘FRAIL’)
- Nutritional Risk Screening (‘NSI-DETERMINE’)
Malnutrition and Frailty Interventions
- Power and Dual Tasking Exercise
- Line/Rhumba Dancing Equivalent
- Community Kitchen-based Nutrition Program
- Psycho-social engagement
- Controls
Supported by health service research grant from
National Medical Research Council, HSRG-
HP17Jun002
TRANSLATION AND IMPLEMENTATION PROJECT:
COMMUNITY-BASED MALNUTRITION AND FRAILTY
SCREENING AND INTERVENTION PROGRAM
In progress

29. Talking Points
 Biological Ageing
 Global Problems of Ageing
 Frailty
 Dementia
 Successful Ageing

30.  2010: 35.6 million cases
 7.7 million new cases annually
 One new case every 4 seconds
 Increase over next 20 years
 Majority of persons with
dementia (PWD) in the world
live in Asia and developing
countries
 60% in 2001
 70% in 2040
35.6
65.7
115.4
Millions
Source: Alzheimer’s Disease International
Dementia worldwide

31. Alzheimer’s Association: alz.org/braintour
Significant impairment in:
• Memory
• Communication and language
• Ability to focus and pay attention
• Reasoning and judgment
• Visual perception
• Alzheimer’s disease
• Vascular dementia
• Mixed dementia
• Fronto-temporal dementia
• Lewy Body dementia
• Others
Dementia

32. Plagues and tangles Cerebral vascular disease
Underlying disease processes

33. Brain structural and functional changes are evident years
before clinical manifestations of dementia

34. • No curative treatment
• Available drug therapy have limited
effectiveness
• Treatment targets are shifting towards
pre-dementia (mild cognitive
impairment) and early dementia
Treatment and Prevention: Paradigm Shift

35. • Preventive Lifestyle, Behaviour and Risk
Factor Change
• Can we slow down cognitive decline?
– Delay dementia onset by 2 years, reduce
prevalence by 20%
– Delay dementia onset by 5 years, reduce
prevalence by 50%
• Can we expand our cognitive reserve
and protect ourselves against dementia?
Treatment and Prevention: Paradigm Shift

36. Dementia Control Strategies
• Slow cognitive decline by modifying
underlying AD and CVS pathological
process
• Increase brain and cognitive reserve:
create surplus buffering capacity

37. Life Course Perspective

38. Lifetime Risk and Protective Factors
• Genetics: APOE-e4
• Socio-demographic: age, ethnicity, low education
• Lifestyle behavior: physical activity
• Social engagement: living alone, loneliness, marital
status, active work employment
• Cognitive-stimulating activities
• Psychological: stress, depression
• Medical: medical conditions and drugs
• Cardio-metabolic: obesity, hypertension, diabetes,
insulin resistance, metabolic syndrome
• Frailty
• Nutritional: malnutrition, folate, B12, omega-3 PUFA,
tea, curcumin, etc
SLAS

39. Lifestyle and Behavioral Factors
Cognitive Reserve
Education is a major determinant of
cognitive functioning and eliminates
ethnic differences in cognitive
performance
Higher level of leisure time physical,
social and productive activity is
associated with less cognitive decline
Int Psychogeriatr. 2008 Jan 11;:1-15.
Am J Geriatr Psychiatry. 2007 Feb;15(2):130-9.

40. Psycho-social Factors
Social engagement
Elderly persons living alone die earlier
Single and widowed men are more
likely to be cognitively impaired
Retirement age elderly who are actively
engaged in paid or volunteer work are
less depressed, less cognitively
impaired, have higher subjective
wellbeing and life satisfaction
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Men Women
Married Divorced Single Widowed
ODDS RATIO FOR COGNITIVE IMPAIRMENT
15.5
18
30.2
84.5
4.9
12.3
34
92.2
7.6 7.9
41.3
92.9
0
20
40
60
80
100
Depressive
Symptoms
Cognitive
decline
Positive Mental
Well-Being
High Life
Satisfaction
Retired without voluntary work
Retired with voluntary work
Still working
Depressive symptoms: Geriatric Depression Scale ≥5
Positive mental well-being: SF-2 MCS scores (upper one third)
Cognitive decline: drop of MMSE score ≥2 points
WORK, RETIREMENT AND VOLUNTEERISM
Hazard Ratio=1.66
(95% Confidence intervals: 1.05 – 2.63)
SURVIVAL PROBABILITY
BMC Geriatr. 2015 Oct 15;15(1):126.
Dement Geriatr Cogn Disord Extra 2014;4:375-384
Age Ageing. 2009 Sep;38(5):531-7.

41. Environmental factors
Neighborhood environment
Older people with higher level of
physical activity and those with higher
cognitive functioning were more likely
to be found living in neighborhoods
with a high density of, close proximity
and easy accessibility to a greater
diversity of amenities and facilities.
Int J Behav Nutr Phys Act. 2015 Sep 15;12:108.

42. Biological and Clinical Factors
Metabolic syndrome and diabetes
Metabolic syndrome predicts
increased risk of incident MCI and
conversion of MCI to dementia
Diabetes is associated with increased
prevalence and incidence of MCI and
dementia
MS- MS+
0
10
20
30
40
50
Incident MCI
Adjusted OR=1.546, p=0.039
Metabolic Syndrome
HR adjusted for sex, race, age,
education, ethnicity, APOE
JAMA Neurology 2016
MS- MS+
0
10
20
30
MCI Progression to Dementia
Adjusted OR=4.25, p=0.002
JAMA Neurol. 2016 Apr ;73(4):456-63.

43. Nutritional Factors
Vitamin B
Immediat
e Recall
Delay
Recall
Verbal
Learning
Forgetting
%
Language
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
Global Language
Executive
Control
Processing
Speed
Visuo-
construction
-0.35
-0.25
-0.15
-0.05
0.05
Feng L, Isaac V, Sim SK, Ng TP, Chee MW. Am J Ger Psychiatr (2013)
Cerebral White Matter Volume
Increasing Folate is positively associated
with memory, learning and language
Increasing Homocysteine is associated
with deficits in processing speed and
visuo-spatial construction and reduced
cerebral white matter volume
Increasing Folate is associated with
better balance, gait, and IADL
independence
Am J Clin Nutr 2012 96: 1362-1368.
Am J Clin Nutr. 2006 Dec;84(6):1506-12.
Neuroimage 2009; May, 46,1: 257-269.

44. Nutritional Factors
Functional Foods
0.00
0.20
0.40
0.60
0.80
1.00
1.20
None Low Medium High
T
ea
OR of Cognitive Decline
Ng TP
, et al. Am J Clin Nutr. 2008, 88: 224-31.
Never or
non-daily Daily
0
0.5
1
1.5
* Adjusted for: age, gender, education, comorbidity, hypertension, diabetes,
cardiac diseases, stroke, smoking, alcohol drinking, depression, APOE status,
nutritional status, level of leisure activities, baseline MMSE and follow-up
duration
J Nutr Health Ageing. (2010)
Omega-3 PUFA
OR of Cognitive Impairment
Higher levels of consumption of
omega-3 PUFA (supplements), tea
and curry are associated with
lower prevalence of cognitive
impairment or cognitive decline
Am J Clin Nutr. 2008, 88: 224-31.
Am J of Epidemiol 2006;164,9:898-906.
J Nutr Health Aging. 2011;15(1):32-5.

45. • Be physically active, exercise regularly
• Avoid social isolation, be socially engaged
• Stay mentally active, keep learning new things
• Monitor and correct waist circumference, high
blood pressure, glucose and lipids and metabolic
syndrome
• Ensure adequate protein-calorie, micronutrients
and anti-oxidant intake
• Design cognition-friendly neighbourhoods
Ageing Without Dementia

46. ©
SLAS MCI (Pre-dementia) Risk Prediction Questionnaire
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10-11
PROBABILITY
OF
MCI
%
RISK PREDICTION SCORE

47. • L
• Launched in July 2018
• Pre-dementia risk scoring calculator
• Multi-Domain Intervention (MDI)
• Currently reached out to 93 senior
activity centres, working with 13
centres
• 335 persons screened, 203 gave
high 6+ risk score, 78 high risk
individuals participating in MDI
National Innovation Challenge (NIC) Project
EARLY DETECTION AND MULTIDOMAIN INTERVENTION FOR DEMENTIA
3. Cognitive Training
• Brain training mobile app (“Memorie”) coupled with EEG
monitoring headset “SenzeBand”
• Brain-training games targeted at attention, memory,
multi-tasking, decision-making and spatial skills
• Monitors users’ cognitive performance through brain
activity, behavioural and game performance
2. Mind-body dual tasking exercises
• ‘MindFun’ - cognition and mental
skills stimulation
• ‘MindGym’ - mind-body physical
movement
1. Nutritional guidance programme:
• Educational, behavioral and
motivational coaching
• Digital online platform

48. Talking Points
 Biological Ageing
 Global Problems of Ageing
 Frailty
 Dementia
 Successful Ageing

49. Healthy life expectancy
 Increasing numbers of older people
live beyond their expected lifespan
 Can we live longer yet stay healthy?
 Research: Extend healthy life
expectancy (healthspan)
 Policy action: Successful ageing /
active ageing

50. Healthy life expectancy
• “Compression of morbidity”
(James Fries, 1983)
• In general, people who postpone the onset of a
major illness to a later age spend less time in
disability before they die.
• Health can be extended well into the ninth decade
of life, with illness and disability compressed into a
period shortly before death.
Does living longer inevitably mean more years of disability?

51. Clues to investigating healthy ageing
1. Centenarians
• More people are living beyond 100
• Characteristics:
‒ Survivors
‒ Delayers
‒ Escapers
2. Successful ageing
• a minority of older people
successfully avoid age-related disease
until late in life, and continue to
remain healthy and function well

52. “Successful Ageing”
Biological, sociological and psychological theories and models
Rowe and Kahn:
• Focuses on physical and mental health functioning
• Avoidance of disease
• Maintenance of high level of physical
and cognitive functioning
• ‘Selective optimization with compensation’
– compensatory strategies in the face of challenges and depleting reserves
– strategic selection of activities, maximizing reserves.
• Resilience:
– ability to adapt to and cope with stress and adversity in late life
– ability to appropriate psychological social, cultural, and physical resources
to sustain well-being
Continuity theory
• Carrying forward values, lifestyles and
relationships from middle to later life;
• Remain socially engaged, adopting
new social roles and activities,
maintaining high levels of social
activity, interaction and participation

53. Successful Ageing
Resilience, Stressful Life Events And
Subjective Well-being
Resilience Factors:
(1) Optimism and competence
(2) Commitment and perseverance
(3) Independence and self-esteem
Aging Ment Health. 2015 Jan 6:1-10.
Resilience moderates the
effects of life event stress on
depression, mental health
functioning

54. Successful ageing
Retirees who remain mentally and physically active
show better well-being
0
0.5
1
1.5
2
2.5
3
3.5
4
Depressive Symptoms
Retired without voluntary work
Retired with voluntary work
Still working
Covariates in general linear model: age (<62 or >=62), education, gender, social network and support, general
health status, and physical functioning.
For cognitive status: + vascular risk factors/ events and depression
20
25
30
Cognitive (MMSE) score
Retired without voluntary work
Retired with voluntary work
Still working
40
50
60
Positive Mental Wellbeing (SF-12 MCS)
Retired without voluntary work
Retired with voluntary work
Still working

55. SUCCESSFUL
AGEING
PERCEPTION AND VALUES
Many more older adults perceived themselves
to age successfully even though they were not
determined to be successful agers by objective
criteria
FACTORS FOR SUCCESSFUL AGEING:
Physical
Health
Financial
Stability
Fulfilling marital /
significant
relationships
Chinese Malay Indian
Percent
The most important factor for successful ageing for me is:
Malays are poorer and physically less
healthy but perceive themselves to
age successfully more than Chinese
• Chinese are more likely to consider
physical health,
• Malays are more likely to consider
fulfilling relationships,
• Indians are more likely to consider
financial stability
as the most important factor for successful
ageing
ETHNIC CULTURAL INFLUENCE

56. Q&A
Discussion
Thank You

59. Hypothesis:
The burden of lifetime illness may be compressed into a shorter period
before the time of death, if the age of onset of the first chronic infirmity can
be postponed.