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
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
IGF-1 production in liver
Phosphoinositide-3-kinase
FOXO1-FOXO3 transcription factors
Cellular growth and proliferatoin
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 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
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
............................................................................
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
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
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
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