Effect of lifestyle modification

: search for evidence

Nayanjeet Chaudhury, MD,MPH Director M&E and Health Services Delivery

Population Services International, India

Certified Personal Trainer (ACSM)

Certified Aerobics Trainer (Reebok)

Aging, Disease & Free Radicals, • Aging is the accumulation of diverse deleterious

changes in the cells and tissues with advancing

age that increase the risk of disease and death. (Harman, D. (2001) Aging: Overview. Annals of New York Academy of Sciences , 928, 1-21. )

• Our expected lifespan at birth and/or the rate of

aging are influenced by – Individual genetic backgrounds and/or

– environmental factors influence.

(Gerstenblith G. Cardiovascular Aging: What We Can Learn From Caloric Restriction⁎. J Am Coll

Cardiol. 2006;47(2):403-404)

Ageing and lifespan

The inherent aging process limits

• Average life expectancy at birth to about 85 years

• and the Maximum life span to around 122 years.

Harman 2001

Improved nutrition

Economic and social uplift

Better living conditions

Improved sanitation

Housing

Environmental protection

Conventional methods of increasing life span

Although in developing countries, these are primary concerns, they

are progressively unsuccessful in prolonging life in developed countries

beyond a certain age limit.

Who’s the culprit?

• A possible determinant – Overproducation of the Free Oxygen Radicals

or Reactive Oxygen Species)

• An important mediator of cell damage and

consequently many disease states :

– Cancer & Diabetes (mitochondrial Oxidative stress)

– Atherosclerosis and chronic inflammation

(inflammatory oxidative conditions )

– Ischemia (xanthine oxidase-induced damage)

Valko et al. Free radicals and antioxidants in normal physiological functions and human

disease. Int J Biochem Cell Biol. 2007;39(1):44-84. Epub 2006 Aug 4.

Caloric Restriction

• CR can greatly increase the longevity of

rodents and invertebrate model systems (Frankel S and Rogina B (2006) Sir2, caloric restriction and aging.Pathol Biol (Paris) 54(2):55-7)

• precise biological mechanisms and

applicability to humans remain unknown.

[Roth, G. S., Ingram, D. K. and Lane, M. A.(2001) Caloric Restriction in Primates and Relevance

to Humans.Annals of the New York Academy of Sciences 928:305-315 (2001).]

Rodent studies

• Purified diet with 22% casein was offered to rats from the 21st day of life in ad libitum or in restricted amounts.

• These regimens were either maintained throughout life or changed at 70, 300, or 365 days of age.

21 days old rats

Restricted diet

from 21 to 70 days

Followed by

Ad libitum feed

Ad libitum

feed

Normal lifespan Increased lifespan

400 + days

•Dietary experiences early in life influence Length of life in rats

Ross, M. H.( August, 1972).Length of life and caloric intake. The American Journal of Clinical Nutrition 25, 834-838

Primate studies on caloric

restriction and aging

• Conclusive evidence yet to come

• Results similar to rodent studies

• Promising outcomes shown in age related

diseases e.g.Diabetes, CVD, osteoporosis

• Monkeys on CR show

– Decreased Fasting glucose and insulin

– Increased insulin sensitivity

– Change in body fat to favor less risk for CVD

Lane, M.A., Black, A., Handy, A., Tilmont, E. M., Ingram, D.K., Roth, G.S.( 2001, April). Caloric

Restriction in Primates. Annals of the New York Academy of Sciences 928(1), 287-295.

Early life, CR and diseases • Diseases that have origins in events of early life:

– Atherosclerosis, coronary heart disease, hypertension,

breast and prostate cancer, Alzheimer disease, Parkinson

disease, essential hypertension, cataracts, amyloidosis,

diabetes mellitus, and amyotrophic lateral sclerosis

(Many of these are diseases of adulthood that shorten life).

(Harman, D. (2001) Aging: Overview. Annals of New York Academy of Sciences , 928, 1-21. )

• CR primates will be less likely to incur these age-

related diseases and may in fact be aging more

slowly than fully fed counterparts. [Roth, G. S., Ingram, D. K. and Lane, M. A.(2001) Caloric Restriction in Primates and Relevance to

Humans.Annals of the New York Academy of Sciences 928:305-315 (2001).]

• Caloric Restriction(CR) and CR-like effects can

significantly reduce mortality in primates by

inducing a physiological state that protects

against age-related disease in various tissues,

including the liver, heart, and the brain.

Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, et al. (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489: 318–321

Fructose controversy

Multivariate relative risk of incident gout in 46393 men from

health professionals follow-up study, according to fifths of free

fructose intake in subgroups. Reference group for comparisons

was men in lowest fifth of fructose intake and (top) with body

mass index <25 kg/m2, (middle) no alcohol use, and (bottom)

total daily dairy intake ≤1.6 servings. Relative risks were

adjusted for age, total energy intake, bodymass index, diuretic

use, history of hypertension, history of renal failure, intake of

alcohol, intake of total vitamin C,and percentage of energy from

total carbohydrate and protein

Choi and Curhan. Soft drinks, fructose

consumption, and the risk of gout in men:

prospective cohort study. BMJ. 2008; 336

(7639): 309–312.

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Intake of added sugars correlates closely with the

rise in obesity, metabolic syndrome, and diabetes

Johnson et al. ,Sugar, Uric Acid, and the Etiology of Diabetes and Obesity. Diabetes 62:3307–3315, 2013

Concept of Energy Balance

Physical Activity and Health

• Like Caloric Restriction, regular physical

activity has been shown to increase

lifespan in animal models

J Gerontol (1983) 38 (1): 36-45. doi: 10.1093/geronj/38.1.36

Philadelphia interdisciplinary longevity study of more than

1300 male rats showed:

• For every 10% reduction of Body weight there was a

13.5% gain in life expectancy

• For every 10% gain in body weight there was a 13.5%

reduction in life expectancy

Ross, M. H.( August, 1972).Length of life and caloric intake. The American Journal of Clinical Nutrition 25, 834-838

Lifestyle modification – evidence for prevention

Variable Evidence for

Inverse

Dose-Response

Relationship

Category of

Evidence

All-cause mortality Yes C

Cardiovascular and coronary heart disease Yes C

Blood pressure and hypertension Noa B

Blood lipids and lipoproteins Insufficient

data

Coagulation and hemostatic factors Insufficient

data

Overweight, obesity, and fat

distribution

Yes C

Type 2 diabetes mellitus Yesb C

Colon cancer Yes C

Low back pain, osteoarthritis, and

osteoporosis

Insufficient data

Quality of life and independent living

in older persons

Yes C

Depression and anxiety Noa B

Lifestyle modification – evidence for prevention

Variable Evidence for

Inverse

Dose-Response

Relationship

Category of

Evidence

All-cause mortality Yes C

Cardiovascular and coronary heart disease Yes C

Blood pressure and hypertension Noa B

Blood lipids and lipoproteins Insufficient

data

Coagulation and hemostatic factors Insufficient

data

Overweight, obesity, and fat

distribution

Yes C

Type 2 diabetes mellitus Yesb C

Colon cancer Yes C

Low back pain, osteoarthritis, and

osteoporosis

Insufficient data

Quality of life and independent living

in older persons

Yes C

Depression and anxiety Noa B

Category A: Evidence is from endpoints of well-designed randomized clinical trials (RCTs)

Category B: Evidence is from endpoints of intervention studies that include only a limited number of RCTs,

post hoc or subgroup analysis of RCT, or meta-analysis of RCTs.

Category C: Evidence is from outcomes of uncontrolled or nonrandomized trials or observational studies.

Category D: Expert judgment is based on the panel's synthesis of evidence from experimental research

described in the literature and/or derived from the consensus of panel members based on clinical

experience or knowledge that does not meet the listed criteria.

a No indicates a lack of evidence for a “dose response” for the relationship between the health outcome

and physical activity; it does not indicate the absence of a favourable relationship.

b Inverse dose response for primary prevention, but not for improvement in blood glucose control among

diabetics

Am

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ine;

Fatty Acid Complement

administered in the body

Diacyl Glycerol and Ceramide

Highly Bioactive and Activates pro inflammatory

pathway

Inhibits Insulin signaling and

promotes fatty acid mediated Insulin

Resistance

Intra Muscular Tri Glyceride

(IMTG)

Innocuous Fatty acid metabolite

Increases Insulin

sensitivity

Recent Studies in Immunology and Bio-signaling

(Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance S. Schenk and

J.F. Horowitz; Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance; The Journal of Clinical Investigation, Volume 117 Number 6 June 2007)

Sedentary group Exercise group

Fatty Acid Complement

administered in the body

Diacyl Glycerol and Ceramide

Highly Bioactive and Activates pro inflammatory

pathway

Inhibits Insulin signaling and

promotes fatty acid mediated Insulin

Resistance

Intra Muscular Tri Glyceride

(IMTG)

Innocuous Fatty acid metabolite

Increases Insulin

sensitivity

Recent Studies in Immunology and Bio-signaling

Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance (S. Schenk and J.F. Horowitz; 2007)

Sedentary

group

Exercise group

REDUCTION IN THE INCIDENCE

OF TYPE 2 DIABETES WITH

LIFESTYLE INTERVENTION OR

METFORMIN

The New England Journal of Medicine.

Volume 346, Number 6, 2002

pp 393-403

Evidence of lifestyle modification

Objectives

Does a lifestyle intervention or treatment

with Metformin, prevent or delay the onset

of Diabetes?

Do these two interventions differ in

effectiveness ?

Does their effectiveness differ according

to age, sex, race or ethnic group?

Inclusion Criteria

Age : ≥ 25 years

BMI : ≥ 24 kg/m2

BMI : ≥ 22 kg/m2 for Asians

FBS : 95-125 mg%

PPBS : 140-199 mg%

Exclusion Criteria

Taking medicines known to alter glucose

tolerance.

Had illness which could seriously reduce

life expectancy or their ability to

participate in the trial.

The Four Step Screening and

Recruitment Process ( Ref. 6)

Interventions

Random allocation of participants in three

groups :

SLR plus Metformin

SLR plus placebo

Intensive lifestyle modification program

Randomized Clinical Trial: 27 centers

Four Step Screening & Recruitment

Process

Eligible Participants

Random Allocation in three groups

Standard lifestyle

& Metformin

N=1073

Standard lifestyle

& Placebo

N=1082

Intensive

Program of

lifestyle modifin

N=1079

Diabetes Prevention Programme Study

Goals for the Intensive lifestyle

intervention

A weight reduction of 7 % of the initial

body weight.

To engage in physical activity of moderate

intensity for at least 150 mins. per week.

Session No. Activity

1 Getting started being active

2 Move your muscles

3 Being active – a way of life

4 Be a fat detective

5 Three ways to eat less fat

6 Healthy eating

7 Take charge of what’s around you

8 Tip the calorie balance

9 Problem solving

10 Four keys to healthy eating out

11 Talk back to negative thoughts

12 The slippery slop of lifestyle change

13 Jump start your activity plan

14 Make social cues work for you

15 You can manage stress

16 Ways to stay motivated

Outcome Measures

Diagnosis of Diabetes : FBS ≥ 126 mg%

or Post load test value of ≥ 200 mg%

The values were also confirmed within six

weeks by same tests, done second time.

The diagnosed participants would be

monitored with FBS.

Outcome Measures.. (contd.)

Levels of leisure physical activity were assessed with Modifiable Activity Questionnaire.

The calculations were done by multiplying duration with frequency as well as MET.

Daily calorie intakes from various sources were also assessed.

MET

Physical Activity MET

Light Intensity Activities < 3

sleeping 0.9

watching television 1.0

sexual activity 1.3

writing, desk work, typing 1.8

walking, less than 2.0 mph (3.2 km/h), level ground, strolling, very slow 2.0

Moderate Intensity Activities 3 to 6

bicycling, stationary, 50 watts, very light effort 3.0

calisthenics, home exercise, light or moderate effort, general 3.5

bicycling, <10 mph (16 km/h), leisure, to work or for pleasure 4.0

bicycling, stationary, 100 watts, light effort 5.5

Vigorous Intensity Activities > 6

jogging 7.0

General calisthenics (e.g. pushups, situps, pullups,jumping jacks), heavy,

vigorous effort 8.0

Running, jogging in place 8.0

Measuring Leisure Physical Activity

Discussion

The incidence of Diabetes was reduced by 58% and 31% in lifestyle intervention group & metformin group, respectively.

The results were similar for all age, sex, race & ethnic groups.

The incidence of DM was higher in placebo groups, than anticipated.

Role of metformin as well as lifestyle intervention, in prevention of T2DM was established.

DPP as the forerunner for the Look AHEAD trial

aDPPDiabetes Prevention Program.

bAHEADAction for Health in Diabetes.

cMean follow-up of 3.0 years (3,17).

dMean follow-up 1 year (4,7).

eHbA1chemoglobin A1c.

fNAspecific results not available;

g0.001 compared with control group.

hTo convert mg/dL glucose to mmol/L,

multiply mg/dL by 0.0555. To convert

mmol/L

glucose to mg/dL, multiply mmol/L by 18.0.

Glucose of 108 mg/dL6.00 mmol/L.

iLDLlow-density lipoprotein.

jTo convert mg/dL cholesterol to mmol/L,

multiply mg/dL by 0.0259. To convert

mmol/L

cholesterol to mg/dL, multiply mmol/L by

38.7. Cholesterol of 193 mg/dL5.00

mmol/L.

kNSnot significant.

lHDLhigh-density lipoprotein.

mTo convert mg/dL triglycerides to

mmol/L, multiply mg/dL by 0.0113. To

convert

mmol/L triglycerides to mg/dL, multiply

mmol/L by 88.6.

(Linda M., et al, Implications of the Diabetes Prevention Program and Look AHEAD Clinical Trials

for Lifestyle InterventionsJ. A. D. A, 2008, pp 66,72)

.

Mean percentage

reduction in initial

weight over 1 year

for participants

assigned to

sibutramine alone,

lifestyle modification

alone, combined

therapy, or

sibutramine plus

brief therapy.

Wadden et al 2005. Randomized Trial of Lifestyle Modification and Pharmacotherapy

for Obesity. N Engl J Med 2005; 353:2111-2120

Lifestyle modification vs pharmacotherapy

CHALLENGES WITH LIFESTYLE

MODIFICATION

• Lack of trained manpower

– Principally in research and hospital settings

• Needs multidisciplinary approach.

• Translating findings from clinical trials

into primary care and community

practice – greater challenge.