Epigenetic and molecular Epigenetic and molecular

mechanisms of vitality increasemechanisms of vitality increase

Prof. Vladimir Khavinson

President of the International Association of

Gerontology and Geriatrics - European Region

Member of the Russian and Ukrainian

Academies of Medical Sciences

St. Petersburg Institute of Bioregulation and Gerontology

Pavlov Institute of Physiology, Russian Academy of Sciences

http://www.khavinson.ru

khavinson@gerontology.ru

Potential increase in the average

human lifespan up to the specific limit

(biological reserve)

Khavinson V. Peptidergic regulation of ageing (2009)

Technologies and products for

longevity

1. Low calorie diet

2. Antioxidantes and vitamins

3. Peptide bioregulators

4. Metformin

5. Melatonin

6. Telomerase activators

7. Stem cells

Scientifically validated

Under investigation

The scheme of peptide regulation of vital activity

Harmful factors(stress, environment,

radiation, etc.)

Decreased gene

activity

Decreased protein

synthesis

Decreased organ

function

Decreased vital activity

Peptides(small proteins)

Recovery

The development of pathology and

accelerated aging

Cytomedins® - peptide bioregulators

geroprotectors (pharmaceuticals)

More than 15 million patients were treated with these pharmaceuticals both for

prevention and treatment of different pathologic states (from 1982 till 2009).

Cytogens® - synthetic peptides

(pharmaceuticals and food supplements)

Characteristic of peptides

1. Natural origin

2. High specificity

3. Complete harmlessness

4. Microdose

5. Availability production

Developed in the St. Petersburg Institute of Bioregulation and Gerontology

1. Peptide preparations (more than 30)

2. Peptide biologically active supplements (more than 40)

3. Peptide cosmetic (more than 10)

Structures of peptides

Conformations of the peptides Ala-Glu-Asp-Gly (Epitalon), Glu-Asp-Gly (Chonluten), Lys-Glu (Vilon) with optimal minimization energy. Red colour indicates oxygen molecules, blue – nitrogen molecules, black – carbon molecules, light gray - polar hydrogen molecules. Nonpolar hydrogen molecules are not displayed

Epitalon Chonluten Vilon

Basis of discoveryComplementary interaction of peptides with DNA

The formation of hydrogen bonds between nucleotides

and tetrapeptide 5’ATTTC3’-3’TAAAG5’

2,1 nm

DNA-peptide complexes

Localization of peptides in the assumed binding sites of the promoter regions of genes: A - location of Ala-Glu-Asp-Gly (Epitalon) at the site of the DNA 5'-D (GGGAAATTCCTC) -3 '(PDB: 2EZD; Huth et al. 1997); B – localization of Glu-Asp-Gly (Chonluten) at the site of the DNA 5'-D(CATGGCCATG)-3' (PDB: 1BUT; Dornberger et al. 1998); C – localization of Lys-Glu (Vilon) at the site of the DNA 5'-D(GCAGCTTCCTGC)-3' (PDB: 1QMS; Bifulco et al. 1998). Peptides molecules are depicted in the form of ball and stick, visualized by the colours of the atoms (blue – nitrogen atom, red – oxygen atom, gray –carbon atom), nonpolar hydrogen molecules are not displayed

Epitalon Chonluten Vilon

Peptide (Epitalon) and DNA

Effect of Retinal Peptides on the induction

activity of the polypotent ectoderm of

Xenopus laevis

Khavinson V. Peptidergic regulation of ageing (2009)

Effect of peptides on protein synthesis

in hepatocytes of rats of different ages

(resource increase)

Khavinson V. Neuroendocrinology Lett. (2002)

Increase in the average lifespan after

application of peptide bioregulators

Anisimov V., Khavinson V., Biogerontology (2010)

The results of 25 experiments

The death of the

control animals (0)

* - p<0.05 as compared to the control

Increase in the vital functions resources of the

organism under effect of peptide

bioregulators

Biological Activity Publications

Increase in the protein synthesis in rat hepatocytes by

42.9%

Khavinson V. Peptides and

ageing. NEL (2002)

Increase in the growth of explants in organotypic

cultures of cells of the animal by 22-42%

Khavinson V. Peptides and

ageing. NEL (2002)

Increase of the number of optional heterochromatin

in lymphocytes of the elderly people by 42.4%

Khavinson V. et al. NEL (2003)

Increase in the number of division of human

fibroblasts by 42.5% and 2.4-fold increase of the

average length of telomeres

Khavinson V. et al. Bul. Exp. Biol.

Med. (2004)

Increase in the lifespan of the animals by 20-40% and

maximal lifespan by 42.3%

Anisimov V., Khavinson V.

Biogerontology (2010), Anisimov

V. et al. Mech. Ageing Dev. (2001)

3.1-fold decrease in the frequency of tumors in

animals, induced by carcinogenic agent

Anisimov V., Khavinson V.

Biogerontology (2010)

Peptide Bioregulation

universal recovery factor of decreased protein

synthesis in a variety of pathogenic processes

and aging

Effect of peptide bioregulators on

morbidity of the employees

(40-60 years) “Avtovaz” (Tolyatti)

when exposed to harmful factors

Main group (450 employees)

received injection within 30 days

(10 injections sequentially), to improve

the functions of the brain - Cortexin,

the immune system - Thymalin,

normalization of endocrine system -

Epithalamin

Control group (400 employees)

received injections within 30 days

(10 injections sequentially)

vitamin B 12, C, D

Changes in morbidity levels

The observation period - 1 year

Control group Acute respiratory

diseases

Total

morbidity

2.4 times2.4 times

2.8 times2.8 times

Effect of peptide bioregulators on the rate of aging

the employees (40-55 years) "Tatenergo" (Kazan)

under the influence of harmful factors

Bashkireva A.S., Konovalov S.S. «Prevention of accelerated aging of working in harmful conditions». Moscow (2004)

Tested with application of bioregulators - 300 people, Control (multivitamins) - 200 people

The observation period - 1 year

* - p<0.05 as compared to the control

Effect of peptide bioregulators on

morbidity in employees (35-60

years) of OAO «Gazprom» («Oren-

burggazprom», «Nadymgazprom»)

under the influence of harmful

factors

Main group (11,192 employees)

received orally for 30 days, 6 peptide

bioregulators to improve the immune

system, brain, blood vessels, bronchus,

liver, cartilage tissue.

Control group (3,000 employees)

received orally for 30 days

multivitamins.

Changes in morbidity levels

The observation period - 1 year

Control group Acute respiratory

diseases

Total

morbidity

2.2.77 timestimes

2.2.33 timestimes

Effect of peptide bioregulators on mortality

in elderly and senile age patients

Khavinson V., Morozov V. Neuroendocrinology Lett. (2003)

Elderly

(60-74 years)

Senile age patients

(75-89 years)

Mo

rta

lity

, %

44,144,1

22,322,3

81,881,8

45,845,8

33,333,3

*

**

Observation period - 12 years Observation period - 6 years

- Control - Epithalamin - Epithalamin + Thymalin

* - р < 0.05 as compared to the control

Effect of Epithalamin on the survival of elderly

patients

IndicesControl group

(Basic treatment)

Main group

(Basic treatment

+ Epithalamin)

Number of patients 40 39

Age of patients before the

study65,1 ± 1,1 64,5 ± 0,9

Survival at 15 years 16 (40%) 26 (66,7%)*

The cause of death of

patients (myocardial

infarction or stroke (%)

83,3 46,2*

* - р < 0.05 as compared to the control

O.V. Korkushko et.al., 2011

Effect of Epithalamin on the survival of elderly

patients

* - р < 0.05 as compared to the control O.V. Korkushko et.al., 2011

Su

rviv

al

rate

(%

)

Basic therapy + complex of peptide bioregulators

Basic therapy (control)

The influence of Epiphysis Preparation

(Ephitalamin) on telomere length

Age of

patients,

years

Normal limits of

telomere length

(b.p.)

Administration of Epiphysis Preparation

Initial value After administration

5-10 13,88-15,89 ـ ـ

25-30 11,78-13,78 ـ ـ

45-50 9,67-11,68 10,53±0,97 11,97±1,32*

60-65 8,09-10,10 9,32±0,82 10,83±1,12*

75-80 6,51-8,52 ـ ـ

90-95 4,93-6,94 ـ ـ

* - p< 0,05 as compared to initial value

#Akiko Tsuji et al. Estimating age of humans based on telomere shortening // Forensic Science International. 2002, 126, 197-199.

Bekaert S. et al. Telomere Attrition as Ageing Biomarker // Anticancer Research. 2005, 25, 3011-3022.

Epiphysis Preparations

Epithalamin (Epinorm) – peptide complex with molecular weight 1000-5000 Da extracted from cattle pineal gland. The prep aration is produced in flacons (ampoules) by 10 mg for intramuscular admi nistration. Course of treatment takes 5-10 days (1 injection daily).

Epitalon –Ala-Glu-Asp-Gly tetrapeptide. The preparation is p roduced in ampoules by 100 µg for intramuscular administration. Course of treatment takes 10 days (1 injection daily).

Endoluten – peptide complex with molecular weight 1000-5000 Da extracted from cattle pineal gland. The preparation is produced in capsules by 10 mg for oral administration. Course of treatment takes 10-20 days (by 2 capsules daily).

Age, years (norm)

Investigation

Telomere length (b.p.)

Epiphysis Preparations

Epithalamin Epitalon Endoluten

60-65

(8,09-10,10)

Initial value9,32 ± 0,82

(n=25)

9,61 ± 0,93

(n=19)

9,43 ± 1,12

(n=21)

After treatment 10,83 ± 1,12 * 10,72 ± 1,21 * 10,62 ± 1,32 *

75-80

(6,51-8,52)

Initial value7,33 ± 0,81

(n=21)

7,51 ± 0,91

(n=17)

7,63 ± 0,98

(n=18)

After treatment 8,73 ± 0,78 * 8,91 ± 1,11 * 8,66 ± 1,21 *

The influence of Epiphysis Preparations on

telomere length in patients’ blood cells

* - р < 0,05 – as compared to initial value

Age, years Investigation**

6-OHMS excretion (ng/h)

Epiphysis Preparation

Epithalamin Epitalon Endoluten

60-65 Initial value

410 ± 38

(n=21)

445 ± 43

(n=19)

428 ± 47

(n=17)

After treatment 933 ± 86 * 915 ± 97 * 820 ± 92 *

75-80

Initial value363 ± 41

(n=18)

371 ± 35

(n=22)

348 ± 43

(n=21)

After treatment 690 ± 63 * 615 ± 71 * 580 ± 62 *

The influence Epiphysis Preparations on the

melatonin metabolite 6-OHMS excretion

* - р < 0,05 – as compared to initial value** - norm for people aged 30-39– 1020-1900 ng/h

Enhancement of human life sources

Application of peptide bio-regulators promoted significantly

decrease the rate of aging in humans

(40-55 years old) when exposed to harmful factors and

increase the survival rate of elderly patients (observation

period - 15 years), as evidenced by:

1. Improving physical capacity

2. Reducing the rate of aging of the cardiovascular system

3. The normalization of metabolism

4. Brain function improving

5. Increased resistance to viral diseases

«Prevention of

age-related pathology and

expanding healthy working

life»

Application of peptide bioregulators

to restore the functions of the body

Complex of the basic peptides to enhance the Complex of the basic peptides to enhance the

resource of life and prevention of ageresource of life and prevention of age--related related

disordersdisordersPinealon (brain)Pinealon (brain)

Vesugen (vessels)Vesugen (vessels)

Chrystagen(thymus)Chrystagen(thymus)

Chonluten (lungs)Chonluten (lungs)

Ovagen (liver)Ovagen (liver)

Cartalax (cartilage)Cartalax (cartilage)

The scheme:

1. Pinealon, Vesugen – 10 days

2. Chrystagen, Chonluten – 10 days

3. Ovagen, Cartalax – 10 days

Total 30 days

Health assessment is

conducted before the

application and again

after 4 months.

This is followed by mathematical processing, statistics and

recommendations. Recommended 2 courses each year.

Enhancement of life resources of

Russian Olympic team gymnasts

left to right: А. Shumilova(coach), D. Kondakova, A. Zaripova (coach),

J. Lukonina, Prof. V.Khavinson, E.Kanaeva, V. Schtelbaums (coach),

I. Viner (honored coach of Russia), О. Buyanova (coach), D. Dmitrieva

Peptide application

areas

Domestic animals

Domestic animals

Synthetic preparations

Synthetic preparations SyntheticSynthetic Medical

cosmetologyMedical

cosmetology AvicultureAvicultureSportsmen products

Sportsmen products

Natural preparations

Natural preparations NaturalNatural Preventive

cosmetologyPreventive

cosmetologyAnimal

husbandryAnimal

husbandry

Functional foods and beverages

Functional foods and beverages

PreparationsPreparationsBiologically

active supplements

Biologically active

supplementsCosmetologyCosmetology Veterinary

scienceVeterinary

science NutritionNutrition

CONCLUSION

As a result of 35 years of investigations was discovered a

new group of peptides – signaling molecules, which

epigenetically regulate gene expression and protein

synthesis. This promotes the enhancement of human life

resources and extending working life.

The institutions, where the basic studies were

conducted (35 years)

St. Petersburg Military Medical Academy

(1977-1991), Head - member of the Russian Academy of Medical Sciences

Prof. V. Khavinson

St. Petersburg Institute of Bioregulation and Gerontology

(1992-2012), Head - member of the Russian and Ukrainian Academies of Medical

Sciences

Prof. V. Khavinson

Petrov Oncology Research Institute

(1977-2012), Head - member of the Russian Academy of Sciences

Prof. V. Anisimov

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

(2008-2012), Head – member of the Russian Academy of Sciences

Prof. B. Vanyushin

Gerontology Institute of the National Academy of Medical Sciences of Ukraine

(1992-2012), Head – Academician of the Academy of Medical Sciences of Ukraine

Prof. O. Korkushko

Foreign institutions where some of the studies

were conducted

National Institute on Aging (Baltimore, USA)

Italian National Research Center on Aging (Ancona, Italy)

Institute of Anatomy, Ludwig-Maximilians-University of Munich

(Munich, Germany)

Prince Felipe Research Center (Valencia, Spain)

University of Antwerp, Department of Biomedical Sciences (Antwerp, Belgium)

Prof. Vladimir Khavinson and staff of the Laboratory of Biogerontology

of the St. Petersburg Institute of Bioregulation and Gerontology

THANK YOU

FOR YOUR

ATTENTION !