Preventive effects of vitamin D and herbal extracts on sarcopenia Sunmin Park Dept. of Food &...

Preventive effects of vitamin D and herbal extracts on sarcopenia

Sunmin Park

Dept. of Food & Nutrition, Obesity/Diabetes Research Center, Hoseo University

Quickly emerging into the aging, aged and super-aged society in Korea

• Korean currently in Aging society • Aging society (over 7% of ≥65

years old) - from 2000 (7.2%), 2004 (8.7%), 2005 (9.1%)

• Aged society (over 14% of ≥65 years old) – at 2018 (14.3%)

• Super-aged society (over 20% of ≥65 years old) – at 2026 (20.2%)

• Fastest movement into Super-Aged Society among OECD countries

France

USA

Germany

Japan

Korea

0 20 40 60 80 100 120 140

Aged to Super-Aged So-ciety

Aging to Aged So-ciety

Duration (years)

Avera

ge of O

ECD

Japan

England

France

Ger

man

yUSA

Korea

0

10

20

30

40

Nu

mb

er

of

dia

be

tic

pa

tie

nts

in 1

00

,00

0

pe

op

le

OECD health data, 2006

Increased prevalence of type 2 diabetes in the elderly

30-39 40-49 50-59 60-69 ≥65 ≥700

5

10

15

20

25

Age categories

Ty

pe

2 d

iab

ete

s (

%)

Remarkably elevated prevalence of dementia and stroke in people with older age

Health report of Dept. of Public Health & Welfare, 2010

60-64

65-69

70-74

75-79

80-84

85-89

>900

5

10

15

20

25

30

35

40

Age categories

De

me

nti

a p

rev

ale

nc

e

(%)

20-29 30-39 40-49 50-59 60-69 ≥700

10

20

30

40

50

60

70

Age categories

Str

ok

e p

rev

ale

nc

e (

pe

r 1

,00

0)

Obesity rates of Korean population by BMI

Men (%) Women (%) Total (%)

All 32.6 34.3 25.9

≤20 yrs old 30.9 9.8 20.9

30s yrs old 41.1 34.0 32.5

40s yrs old 41.1 23.1 33.1

50s yrs old 34.5 39.0 38.7

60s yrs old 36.2 34.7 37.5

70s yrs old 29.5 39.1 34.7

≥80 yrs old 20.3 26.7 24.3

Obesity : BMI > 25

Obesity paradox

Adjusted for age, gender, educational level, urban or rural residence, marital status, and status with respect to baseline illnesses; data from > 3 yr follow-up

Zheng et al. N Engl J Med, 2011

Correlation between BMI and %BF for men in 1994 NHANES

BMI represents not only body fat but also

lean body mass

Changes in muscle mass with aging

Lexell et al., 1988

Age (yrs)Age (yrs)

Mu

scle

ma

ss (

X48

) (m

m2)

Current definition of sarcopenia

Loss of skeletal muscle mass

CAUSES :Age, diet, activity, disease and their Combination

Loss of strength

CONSEQUENCES:Falls, functional decline, disability,

and mortality

Criteria of sarcopenia and sarcopenic obesity

Sarcopenia

21 year old Female (BMI = 24.3 kg/m2)

73 year old Female (BMI = 24.5 kg/m2)

Age-associated decline in muscle mass

Increases fat infiltration in muscles without and with sarcopenic obesity

Rossi et al. Obesity, 2010

Diseases related to sarcopenia and obesity

Zamboni et al., 2008

Sarcopenia: What is driving the process?

• Chronic inflammation?• Food intake (protein, calorie)• Hypermetabolism• Pro-inflammatory cytokines (IL-1b, IL-6, TNF-α)

• Decline in anabolic hormones?• GH/IGF-1• Sex steroid hormones

• Free testosterone• DHEA

• Fading effectiveness of insulin

• Loss of innervation?

SARCOPENIA

NEED of Promising treatment options

Prevention or Reversibility ?Partially, yes

VITAMIN D AND SARCOPENIA

What can prevent the sarcopenia ? : A link between vitamin D and sarcopenia

• V-D receptors that bind 1,25(OH)2-D3 exist in skeletal muscle cells • Regulation of Ca transport into the muscle

cells• Uptake of inorganic phosphate for produc-

ing energy-rich phosphate compounds• Protein synthesis

• V-D deficiency – secondary hyper-parathyroidism • Predominantly lower limb muscle

V-D3

25-OH-D3Liver

Blood

Kidney 1,25-(OH)2-D3

(Active form)

(Deficiency indicator)

Results from KNHANES for vita-min D, sarcopenia, and metabolic diseases (CVD and diabetes)

Park S et al. J Nutr Health & Aging, 2014: Stroke risk and sar-copenia

Park S et al. Clin Nutri, 2014: Vitamin D deficiency and sarcope-nia

Park S et al. J Nutri Sci & Vitaminol, 2014 : Vitamin D and GDM

Lee BK et al. Asia Pac J Clin Nutri, 2012: Vitamin D and type 2 di-abetes

Park S & Lee BK, Nutr Res Prac, 2012: Vitamin D deficiency

and CVD

Serum 25-OH-D3 levels with sacopenic states in KNHANES 2008-2010

Men Women0

10

20

30

40

50

60

Normal Class I Class II

25

-OH

-D3

(n

mo

l/L)

N=2,029 N=196 N=784 N=2,582 N=367 N=1,250

Park S et al. J Nutr Health & Aging, 2014

with ≥50 yrs old

ab b a

bc

Daily nutrient intakes by sarcopenic status after covariate adjustment in KNHANES 2008-2010

Men with ≥50 yrs old (n=2,258) Women with ≥50 yrs old (n=3,005)

Normal (SMI>28.9%)

Sarcopenia (SMI≤28.9%)

Normal (SMI>22.6%)

Sarcopenia (SMI≤22.6%)

Total energy (Kcal)

2197 (2154~2240) 1965 (1746~2185)* 1591 (1560~1621) 1447 (1380~1513)**

Protein (g) 76.5 (74.4~78.5) 66.8 (58.4~75.2)* 53.3 (52.0~54.6) 48.3 (45.1~51.5)**

Carbohydrate (g)

358.3 (350.7~365.9) 315.7 (293.4~338.0)** 294.1 (287.9~300.2) 264.3 (252.1~276.6)**

Fat (energy %) 14.2 (13.9~14.6) 14.3 (12.4~16.3) 12.8 (12.5~13.2) 13.9 (12.9~14.9)*

Fiber (g) 9.0 (8.5~9.4) 8.0 (7.0~9.0) 7.3 (7.1~7.6) 6.5 (5.8~7.2)*

ª adjusted for age, residence area, body mass index, smoking and drinking status, education level, regular exercise and walking and use of estrogen and oral pill for women* p<0.05, ** p<0.01 compared with normal subjects

Park S et al. Clin Nutri, 2014

Odds ratio of sarcopenia prevalence by serum 25-OH-D3 levels in KNHANES 2008-2010

Odds ratio

Men (n=2,258) Women (n=3,005)

Model 1a

Continuous per 10 ng/ml lower 25-OH-D3 0.95 (0.59~1.51) 1.46 (1.01~2.12)

Categorized with25-OH-D3

Deficiency (< 15 ng/ml) 0.47 (0.16~1.38) 3.81 (1.61~9.03)

Borderline (15-29.9 ng/ml) 0.50 (0.21~1.20) 2.68 (1.11~6.47)

Normal (≥ 30 ng/ml) 1.00 (Ref) 1.00 (Ref)

Model 2b

Continuous per 10 ng/ml lower 25-OH-D3 1.01 (0.64~1.58) 1.46 (1.01~2.12)

Categorized with25-OH-D3

　

Deficiency (< 15 ng/ml) 0.50 (0.17~1.49) 3.64 (1.48~9.00)

Borderline (15-29.9 ng/ml) 0.587 (0.24~1.44) 2.54 (1.01~6.37)

Normal (≥ 30 ng/ml) 1.00 (Ref) 1.00 (Ref)

aadjusted for age, residence area, body mass index, smoking and drinking status, education level, regular ex-ercise and walking, daily nutrient intakes, body fat and use of estrogen and oral pill for women for model 1. badjusted for all covairates in model 1 plus selected blood tests (parathyroid hormone, cholesterol, TG, HDL, AST, and ALT, glucose, and HOMA-IR) for model 2.

Park S et al. Clin Nutri, 2014

HOMA-IR and total cholesterol with sarcopenia

HOMA-IR for men0

0.5

1

1.5

2

2.5

3

3.5Normal (SMI>25.4%) Class I (SMI 22.8-25.4%)

Class II (SMI<22.8%)

Total chol for women0

30

60

90

120

150

180

210

240


with ≥50 yrs old

a

b b

b ab a

a,b,cDifferent alphabets on the bars indicate significantly differences in each variable.

Odd ratios (95% CI) for cardiovascular diseases by sarcopenic status in KNHANES 2008-2010

Men with ≥50

yrs old

Normal

(SMI>32.0%)

(n=2,029)

Sarcopenia Class I

(SMI 29.0-32.0%) (n=196)

Sarcopenia Class II

(SMI<29.0%) (n=784)

Model 1 Model 2 Model 1 Model 2

Cardiovascular

Disease1.0 (Reference)

1.887

(1.306~2.727)

1.819

(1.242~2.666)

2.516

(1.318~4.800)

2.350

(1.255~4.399

)

Stroke 1.0 (Reference)1.714

(1.013~2.902)

1.656

(0.975~2.814)

3.777

(1.679~8.495)

3.686

(1.721~7.894

)

Miocardial

infarction1.0 (Reference)

1.644

(0.827~3.269)

1.626

(0.795~3.326)

1.240

(0.398~3.856)

1.162

(0.377~3.582

)

Angina

pectoris1.0 (Reference)

1.919

(1.079~3.413)

1.889

(1.065~3.352)

1.534

(0.561~4.192)

1.314

(0.450~3.838

)

# In model 1, adjusted for age, residence area, body mass index, waist circumferences, hypertension, smok-ing and drinking status, education level, regular exercise and walk, protein and carbohydrate intake and use of hormone and oral contraceptive pill for women. In model 2, all covairates in model 1 plus selected blood tests (25-OH-vitamin D, total cholesterol, TG, HDL, AST, and ALT, systolic blood pressure, diastolic blood pressure, blood glucose, and HOMA-IR).


Prevalence ratio of type 2 DM by serum 25-OH-D3 levels in young and old men in KNHANES

<25 nmol/L 50 nmol/L 75 nmol/L0

4

8

12

16

Young men Old menP

rev

ale

nc

e r

ati

o (

%) *

*

*†

*Significantly different from young men† Significantly different among different groups with serum 25-OH-D levels in old men

Lee BK et al., Asia Pac J Clin Nutri, 2012

Serum 25-OH-D3

Summary I

• Vitamin D deficiency is related to sarcopenia in Korean popula-tion, especially men.

• Vitamin D deficiency has a positive relation with sarcopenia.• Sarcopenia shows a positive association with stroke.• Vitamin D deficiency exhibits the increase of CVD and type 2 di-

abetes in the elderly men.

The effect of V-D supplementation on energy and glucose metabolism in GK male rats

Unpublished data

Experimental design

Purchase Provide Energy Catheter HG & EU ScarifyingGK rats assigned expenditure insertion clamps collecting 232±16g diets OGTT tissues

• Goto-Kakizaki (GK) male Rats: non-obese Wistar substrain that develops type 2 diabetes mellitus early in life.• GK rats were provided 40 En% fat diet with 0 IU (No-VD; n=14), 1,000 IU (Normal-VD; n=14), 10,000 IU (Excess-VD; n=14) vitamin D.• Hyperglycemic (HG) clamp : Measure serum insulin levels about at the serum glucose level of 5.6 mmol/L above baseline by glucose infusion.• Hyperinsulinemic euglycemic clamp: 3H-glucose was infused for 30 min for basal state. The mixture of 3H-glucose and insulin (12mU/kg BW/min) was continuously infused for approximately 2 hours. Serum insulin levels reached to 14 ng/mL, and the serum glucose levels were adjusted to 5.6 mM.

0 1 8 8 weeks76

Serum 25-OH-D3 levels and body weight

Series10

100

200

300

400

Bo

dy

we

igh

t (g

)

25-OH-D30

20

40

60

80

100

NO-VD Normal-VD Excess-VD

25

-OH

-D3

(n

mo

l/L)

c

b

a

a,b,cDifferent alphabets on the bars indicate significant differences in each variable.

Visceral fat and brown fat mass

Epididymal fat Retroperitoneum fat Brown fat (X10)0

2

4

6

8

10

12

14NO-VD Normal-VD Excess-VD

(g)

a,bDifferent alphabets on the bars indicate significant differences in each variable.

a

bb

aab

b

a

bb

Lean body mass measured by DEXA

Abdomen Leg0

2

4

6

8

10

12NO-VD Normal-VD Excess-VD

Le

an

bo

dy

ma

ss

(g

)

aa

b

aa

b


Fat mass measured by DEXA

Abdomen Leg0

1

2

3

4

5

6


Fa

t m

as

s (

g)

a

b b

a

b b


Daily energy expenditure and fuel usage

Series10

40

80

120

160


En

erg

y e

xp

en

dit

ure

(K

ca

l/da

y)

Carbohydrate Fat 0

1

2

3

4

5

6

7

8

Ox

ida

tio

n (

mg

/kg

0.7

5/m

in)

ab

a

b

aa

b


Changes of serum insulin levels during hy-perglycemic clamp

a,b,cDifferent alphabets on the bars indicate significant differences in each variable.* Significantly different among the groups.

0 2 5 10 60 900

1

2

3

4

5

6

7


Time (min)

Se

rum

ins

ulin

(n

g/m

L)

AUC of 1st phase AUC of 2nd phase0

1020304050607080


ng

ldL

*min

aa

babc

* *

**

Serum glucose level of 5.6 mmol/L above baseline by glucose infusion

Glucose disposal rates glucose uptake during euglycemic hyperinsulinemic clamp


Glucose infusion rate Glucose uptake0

5

10

15

20

25


mg

/kg

bw

/min

aa

b

ab

a

b

Insulin infusion (12mU/kg BW/min); Maintain serum glucose 90-100 mg/dL

Hepatic glucose output during euglycemic hyperinsulinemic clamp

Basal state Clamped state0

5

10

15

20

25

30

NO-VD Normal-VD Excess-VDm

g/k

g b

w/m

in

P=0.08

Gene related to fatty acid oxidation in gas-trocnemius muscles and BAT


PPAR-α CPT-1 UCP3 TNF-α0

0.5

1

1.5

2

2.5NO-VD Normal-VD Excess-VD

Re

lati

ve

inte

ns

ity

(A

U)

UCP10

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Re

lati

ve

inte

ns

ity

(A

U) aa

b

aa

b

aa

b

aa

b

b

a

b

Summary IIVitamin D deficiency

Lean body mass

Fat mass

Insulin secretion capacity

Glucose uptake

Fatty acid oxidation in skeletal musclesPPAR-α, CPT1, UCP1, UCP3

Disturbance of glucose metabolism

Water extract of Korean mistletoe and body composition in ovariec-tomized rats

Kim et al., Exp Med Biol, 2014

Contents of phenolic compounds and flavonoids

Water extract of

Korean mistletoe

70% methanol extract of

Korean mistletoe

Polyphenols 3.53±0.54 5.86±0.63

Flavonoids 1.32±0.22 2.38±0.31

Betulinic acid ND 0.51 ± 0.00

Oleanolic acid ND 0.89 ± 0.01

Viscothionin 2.71±0.52 ND

Values are means±SD. ND, non-detectable.

(unit: mg/g dry weight)

Experimental design

Purchase OVX Provide Energy OGTT Scarifying 220±14g assigned diets expenditure collecting (8-9 wks old) tissues

• Ovariectomized (OVX) female Sprague Dawley rats OVX rats in all groups were provided 40 En% fat diet with 0.2% (0.2% MIS) or 0.6% water extract of Korean mistletoe (0.6% MIS) or 0.6% dextrin for control. • Normal control : Sham (non-OVX) rats fed 40 En% fat diet with 0.6% dextrin

0 1 9 10 weeks82

OVX 1st week OVX 8th week

Changes of body weight and food in-take

†Significant difference between OVX rats (control) and Sham rats (normal control).

† †

1 2 3 4 5 6 7 80

50

100

150

200

250

300

350

400

450

Control 0.2% MIS0.6% MIS Normal control

Experimental periods (weeks)

Bo

dy

we

igh

t (g

)

† † †

Series10

2

4

6

8

10

12

14

16

Control 0.2% MIS 0.6% MISNormal control

Fo

od

inta

ke

(g

/da

y)

Daily energy expenditure

Con-trol

0.2% MIS

0.6% MIS

Normal control

0

20

40

60

80

100

120

140

Da

ily e

ne

rgy

ex

pe

nd

itu

re (

Kc

al/d

ay

)

CHO oxidation Fat oxidation0

1

2

3

4

5

6

7

8

9

10Control 0.2% MIS0.6% MIS Normal control

(m

g/ k

g0

.75

/min

)

†

†


†

Lean body mass measured by DEXA

a,bDifferent alphabets on the bars indicate significantly differences in each variable.

†Significant difference between OVX rats (control) and Sham rats (normal-control).

Abdomen-4wk Leg-4wk Abdomen-8wk Leg-8wk0

2

4

6

8

10

12Control 0.2% MIS 0.6% MIS Normal-control

LB

M (

g)

aab

b

†

aab

b

†

aab

b

†

aab

b

Immunoblotting in gastrocnemius muscles

Control 0.2% MIS 0.6% MIS Normal

β-actin

p-mTOR

mTOR

p-4E-BP1

4E-BP1

pAMPK

AMPK

Fat mass measured by DEXA

Abdomen-4wk Leg-4wk Abdomene-8wk

Leg-8wk0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5Control 0.2% MIS 0.6% MIS Normal control

Fa

t m

as

s (

g)

†

†

†

†


Genes related to fatty acid oxidation in gas-trocnemius muscles

aab

b

†a

abb

†a ab

b†

PPAR-α CPT-1 SREBP-1 FAS0

0.5

1

1.5

2

2.5

Control 0.2% MIS 0.6% MIS Normal-control

Re

lati

ve

inte

ns

ity

(A

U)

†a

abb

Series10

0.4

0.8

1.2

1.6

TG

(m

g/g

tis

su

e)

a

abb

†

a,bDifferent alphabets on the bars indicate significantly differences in each variable.


Possible action mechanism of V-D and MIS in the skeletal muscles

ER-α

PPAR-α

CPT-1

SREBP-1c

FAS

MIS

MIS

Increase protein synthesis Increase fatty acid oxidation

V-D receptor

V-D

UCP

V-D receptor

V-D

Conclusion

Vitamin D, MIS

Type 2 diabetes CVD

Lean body mass

Fat mass

Improvement of energy and glucose metabolism

Preventive effects of vitamin D and herbal extracts on sarcopenia Sunmin Park Dept. of Food &...

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Transcript of Preventive effects of vitamin D and herbal extracts on sarcopenia Sunmin Park Dept. of Food &...