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The best strategy for 5 000 000 000 people

100 000 people die from aging every day

It is very likely the solution to the problem would be a combination of therapies

Epigenetic regulation of gene expression

Gene transcription regulation

Pharmacological activation/inhibion of aging-associated genes

Interventions in telomerase operation may prolong life

Autophagy

DNA repair

Possible interventions

Comparative biology of aging may provide the solution to the problem of combating aging

Diseases

Aging

Aging leads to death

University of South California Davis

Drosophila average lifespan was increased 2-fold

"Centenarian" mouse lived 2 times longer than regular mice do

Yeast lifespan was increased 10-fold

Andrzej Bartke

Valter Longo

Southern Illinois University

Blanca Rogina

University of South California Davis

Universisty of Connecticut

M. Musculus

Approximately 25 000 genes

S. cerevisiae

3 billion nucleotides in genome - same as human

Approximately 23% of genes have human homologs

99% of genes have human homologs

Average lispan is 2-2,5 years

Average lifespan is 1 week

We can fight aging

D. melanogaster

Growth hormone receptor knockout + caloric restriction = 2-fold life extension

13 767 genes

Approximately 50% of proteins have human homologs

Deletions in RAS2 and SCH9 genes +

caloric restriction = 10-fold life extension

Nematode lifespan was increased 10-fold

Average lifespan is 70 days

Robert Shmookler-Reis

University of Arkansas

Indy gene mutation = 2-fold increase in average lifespan

Lifespan of a nothobranchius fish was pharmacologically increased by 59%

Alessandro Cellerino

C. elegans

Scuola Normale Superiore, Pisa, Italy

Approximately 35% of nematode genes have human homologs

Average lifespan is 2-3 weeks

"Turning off" Age-1 gene = 10-fold life extension

Notobranchius furzeri

Growth hormone

Growth hormone receptpor

IGF-1 production in liver

IGF-1R receptor

IRS1-IRS4

Phosphoinositide-3-kinase

PTEN phosphatase

PDK kinase

AKT, SGK-1 kinases

FOXO1-FOXO3 transcription factors

Cellular growth and proliferatoin

Stress resistance

The most short-lived vertebrate - average lifespan 4-5 months

10% of all genes code for transcription factors

The largest protein family

5-methyl citosine

Adding resveratrol to diet = increase in maximum lispan by 59%

Gene expression regulation

1

Mikhail Blagosklonny

Roswell Park Cancer Institute

We can start rapamycin clinical trials in humans right away

Activation of stress resistance genes leads to life extension

David Harrison

Randy Strong

Richard Miller

University of Michigan

Jackson Lab

University of Texas at Austin

Rapamycin extends lifespan of old mice by 9-14% via mTOR inhibition

Aging processes are extremely complicated

Alexey Olovnikov

Institute of Biochemical Physics RAS, Moscow, Russia

In 1971 hypothesised that telomerase enzyme exists that elongates telomeres

Elizabeth Blackburn

Carol Grader

Jack Szostak

University of California, San Francisco

Johns Hopkins University

Harvard Medical School

2009 Nobel prize laureates in Physiology and Medicine for telomerase discovery

Maria Blasco

Centro Nacional de Investigaciones Oncologicas, Spain

Activation of telomerase extends life of cancer-resistant mice

Biological interventions

SENS solution

Aging damage

..........................................................................................................................

Nuclear DNA mutations

Blocking of telomere elongation

Mitochondrial DNA mutations

Transfer of mitochondrial genes into the nucleous

Intracellular "junk"

Aubrey de Grey

Utilizing bacterial enzymes for aggregate degradation

Development of substances that would identify and brake the cross-links

Protein cross-links in extracellular matrix

............................................................................

SENS Foundation

Extracellular "junk"

Vaccination for aggregate removal by the immune system

Loss of functional cells

Adding stem cells and using other methods of regenerative medicine

Accumulation of non-degradable harmful cells

Immune system stimulation for removing these cells or their "suicide" activation

SENS = Strategies for Engineered Negligible Senescence

Damage removal

2

Активные формы кислорода

Мишени АФК

Fe-S кластеры

ДНК

-SH группы белков

Липиды

Белки

Oxidative stress

TNFα

Фактор некроза опухоли-α

IL-1

Избыточная продукция провоспалительных молекул

Интерлейкин-1

Бактерии

Инфекции

IL-10

Интерлейкин-10

Вирусы

Грибы

Inflammation and infections

Malnutrition

8 175 133

Stress

Temperature stress

Caloric restriction

Low calorie diet (reduction of food amount by 30-40% without malnutrition) increases lifespan and slows aging processes in yeast, nematodes, mice, rats and non-human primates

Metabolism regulation

3

Light regime disturbance

Коротковолновое электромагнитное излучение:

  • Рентгеновское и гамма-излучение

Потоки заряженных частиц:

  • бета-частиц (электронов и позитронов)
  • альфа-частиц (ядер атома гелия-4)
  • протонов
  • других ионов
  • нейтронов
  • мюонов и др.

Ionizing radiation

Cell cycle arrest

Vera Gorbunova and Andrey Seluanov

Rochester University

Rochelle Buffenstein

University of Texas San Antonio

4

Studying the evolution of aging and anti-aging mechanisms

Prevention of stem cell depletion

82 days

Mechanisms of DNA repair

Excision repair

DNA damage types

Single nucleotide damage

Formation of 8-oxo-guanine

Nucleotide pair damage

Nonhomologous end joining

Single- and double strand brakes

Nebel A, Flachsbart F, Till A, Caliebe A, Blanché H, Arlt A, Häsler R, Jacobs G, Kleindorp R, Franke A, Shen B, Nikolaus S, Krawczak M, Rosenstiel P, Schreiber S.

A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians.

Mech Ageing Dev. 2009 Oct

Homologous recombination

Cross-linking between bases in a single strand of different DNA strands

395 долгожителей из Германии

49 генов репарации ДНК, 92 SNP

У многих женщин-долгожителей C аллель в промоторе гена экзонуклеазы 1

Нужно активировать ген экзонуклеазы 1 для продления жизни

Naked mole rat

Heterocephalus glaber

Maximum lifespan is 30 years

Proliferation

100-year-old centenarians didn't lead a healthy life style

Tissue repair

LON protease

Differentiation

Снижение экспрессии и активности протеазы LON с возрастом

Накопление окисленной аконитазы

Расщепляет окисленные белки

Дестабилизация мтДНК

Образование токсичных агрегатов

Cell therapy

Apoptosis

5

Regenerative medicine

Knowledge base on regenerative potential

Tissue engineering

Ana Maria Cuervo

Albert Einstein College of Medicine

3 types of autophagy

Intensification of shaperone-mediated autophagy by activation of heat shock proteins improves hepatic cell function

1

Macroautophagy

2

Microautophagy

3

Shaperone-mediated autophagy

Gordon Lithgow

Buck Institute

Thioflavin T extends nematode lifespan by autophagy and proteolysis activation

Regeneration regulation

Stem cell niche

Growth factors

Small molucules

Genetic regulation

Proteasome

Paul PK, Kumar A.

TRAF6 coordinates the activation of autophagy and ubiquitin-proteasome systems in atrophying skeletal muscle

Autophagy, 2011 May 1, University of Louisville School of Medicine

Ингибирование 6 фактора, ассоциированного с рецептором к фактору некроза опухоли приводит к блокированию атрофии мышц

Claudio Franceschi

Cellular repair

Bologna University, Italy

It is crusial to find a way to reduce chronic systemic inflammation in aging tissues

Reducing chronic inflammation

6

Xenobiotics detoxification

Neuroendocrinal regulation of homeostaasis

Immunity

Free radicals neutralization

Mechanisms of stress resistance

Глутатион

Cверхэкспрессия гена klotho подавляет старение и увеличивает продолжительность жизни через подавление инсулиновогосигналинга и FOXO-зависимую индукцию Mn-SOD

Долгоживущая линия дрозофил methuselah (mth) устойчива к оксидантам и живет на 35% дольше

Долгоживущие мутанты Daf-2 и Age-1 имеют повышенную активность супероксид дисмутазы, каталазы и глутатион-S-трансферазы

Сверхэкспрессия генов Sod1 и Sod2 продлевает жизнь на 30%

2GSH + H O → GS–SG + 2H O

2

Inteventions in immune system aging

Innate

Adaptive

Studying neuroscience

Hormone-replacement therapy

Репарирует окисленные метионины

Tissue repair

Methionine sulfoxide reductase

Search for ways of sustainable nervous system functioning

Neuroendocrinal regulation of aging and anti-aging processes

Cellular repair

Thymic involution

7

Interventions in organ-specific aging processes

Стресс - накопление белков неправильной конформации в люмене эндоплазматического ретикулума

Прионоподобный белок abu-11

Endoplasmatic reticulum stress sensors

0

Creation of a tissue engineered thymus

Ghrelin therapy

Heat shock proteins and shaperons

Wu D, Cypser JR, Yashin AI, Johnson TE

Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans

Experimental Gerontology, 2009 Sep, University of Colorado at Boulder

8

Creation of a knowledge base on biomarkers of aging

Something else

9

Expected growth of geroprotector market

Billion $

GEROPROTECTION

latin "prevention of aging"

Aging prevention at younger ages

Drugs against atherosclerosis, hypertension, Alzheimer's disease and other age-related pathologies

Demand

-

Aging

AGING BIOMARKERS - parameters that reproducibly qualitatively or quantitatively change during aging

loss of stress resistance genes function

Alexey Moskalev

Institue of Biology Komi Science Center UdRAS, Syktyvkar, Russia

Geroprotector market drivers

Drosophila life extension by GADD45 overexpression in the nervous system

Plyusnina EN, Shaposhnikov MV, Moskalev AA (2011) Increase of Drosophila melanogaster lifespan due to D-GADD45 overexpression in the nervous system. Biogerontology

Stress resistance genes

Geroprotection targets

Aging biomarkers

Geroprotector market growth

Young people

Baby boomers

They possess 70% of capital and 80% of money savings in the US

Responsiveness to innovative pharmacological products

Drugs are needed

That will restore our ability to fight stress at older ages

Maria Konovalenko

mariakonovalenko.wordpress.com

Common cause

A living assessment of geroprotector effectiveness is needed

Maria Konovalenko

By 2030 the number of people aged 60+ will exceed 1 billion

mkonovalenko

%

Geroprotector criteria

1950

2007

2050

Widely accepted is ONE - maximal lifespan increase of a model animal

Part of population aged 60+ in the world, 1950-2050

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