Organised by: Co-Sponsored: Malaysian Healthy Ageing Society
Healthy Ageing from molecules to hormesis Aarhus University - library Aarhus University – science park Biogerontology, class Molecular Biology Dept Suresh Rattan, PhD, DSc Editor-in-Chief, Biogerontology Department of Molecular Biology and Genetics Aarhus University, Denmark
Sociological effectors and implications Psychological modulators Biological basis of ageing and longevity
Ageing from a biological perspective…. • When ageing occurs in life, and why? • What happens during ageing? • What is the molecular basis of ageing ? • How to intervene….
Lifespan of an individual is limited...
Types of lifespan 1. 2. Examples Average LS Maximum LS Fruitflies 30-40 days 80 days Rats/mice 20-24 months 36 months Humans 75-80 years 122 years Besse Cooper – 26 Aug. 1896
Three types of lifespan 3. Essential Lifespan Maximum Lifespan – within a cohort (ELS) Average Lifespan of a Species Lifespan required cohort / population in evolutionary terms 40 - 45 years Humans
If an organism lives beyond essential lifespan of its species, that is when ageing sets in - biologically
2007 Growth-maturation 1979-1984 2005 My own growth, maturation, immortality, & ageing.... 2011 Looking forward to..., 2041 My route to immortality – Anuresh
Many factors affect ageing and longevity of an individual • Lifespan of parents and grand-parents (genetic influence ca. 25%) • Age at first child birth • Level of education • Social network partner, children, siblings, friends • Self-perceived and socially-perceived age and health status
Programmed to age and die? We are not programmed to age and die. There are no gerontogenes whose sole function is to cause ageing and eventual death.
To understand ageing and death, we must understand the mechanisms of life and survival… Oxygen metabolites ROS, other free radicals Nutritional metabolites glyoxal, methylglyoxal, carbonyls acids, Maintenance and repair systems aldehydes Biochemical infidelity • Genomic stability errors, modifications, misfolding • Epigenomic stability • Protein stability Sources of damage • Macromolecular turnover • Free radical counteraction
Maintenance and repair systems create homeodynamic space Growth, development and Homeodynamic space maturation…. Vulnerability zone
Biological characteristics of the homeodynamic space 1. Stress response and buffering capacity 2. Damage prevention, repair and removal 3. Continuous remodelling and adaptation
Age-related changes have been well described… • Species/populations bacteria, fungi, plants, insects, worms, fish, bird, mammals • Individuals , fruitflies, nematodes, rats, mice, monkeys, humans • Systems immune, nervous, cardiovascular, endocrine, reproductive, skeletal • Organs and tissues brain, heart, liver, lungs, skin, kidney, • Cells fibroblasts, keratinocytes, epithelial cells, osteoblasts, T cells, glial cells • Organelles nucleus, mitochondria, lysosomes, endoplasmic reticulum, ribosomes • Macromolecules DNA, RNA, proteins, carbohydrates, lipids
The Hayflick system Ageing of cells in culture Sparse culture Confluent culture young: less than 30% lifespan completed with Len Hayflick - Warsaw, Oct. 2007 35 30 25 20 15 10 5 0 0 100 200 300 400 Days in culture middle aged: between 60 and 80% lifespan completed Control cells 37¼C 41¼C treated cells 42¼C treated cells Our research work is on the ageing and anti-ageing of human cells in culture.... Skin fibroblasts, keratinocytes, vascular endothelial cells, osteoblasts, bone marrow stem cells old: more than 95% lifespan completed
Ageing occurs at all levels of biological organisation, but differently…
Vulnerability zone Vulnerability zone Homeodynamic space Homeodynamic space Ageing is the shrinkage of the homeodynamic space
Ageing is the common factor for several diseases Alzheimer’s Parkinson’s Diabetes Cancer Cataract Osteoporosis Sarcopenia Cardiovascular problems
Shrinkage of the homeodynamic space occurs due to the accumulation of molecular damage • DNA damage mutations, epimutations , base modifications, strand breaks… • RNA damage base modifications, miscoding, missplicing … • Protein damage Amino acid modifications (spontaneous, oxidative, sugar-mediated etc) , misincorporations, misfolding … • Other macromolecular damages Lipid-protein conjugates, Advanced glycation endproducts (AGE)...
Questions that need to be answered… 1. What is the relevance and significance of different types and levels of molecular damage in physiological terms? Implications in prevention, reversion, enhancement
Questions that need to be answered… 2. What is the nature of young and healthy molecular networks which comprise the homeodynamic space? Biomarkers of health, frailty, remodelling, adaptation
Ageing interventions can be: 1. Wishful thinking and miracles 2. Piecemeal remedies and replenishments 3. Preventive strategies and interventions.
Piecemeal remedies Partial or complete serial Better material organs replacement. Stem cell therapies
A formula for eternal youth E = G M C 2
G Genes and gene-networks Intelligent Re-designing...!!! 1. to repair molecular damage 1. to remove molecular damage 2. to neutralise damaging agents Creating new parts?
Improving M = milieu in which genes operate M in E = G M C 2 Milieu is….. Cosmetics and cosmeceuticals • intra-cellular • inter-cellular • systemic • body level • psychological level • group level • population level • global • universal ????? Drugs and nutriceuticals • Vitamins • Hormones • Bio-extracts/spices • Natural and synthetic antioxidants
A major shift in approach towards ageing interventions…. Instead of having an “enemy - oriented” approach against ageing, the effort is now on “friend - oriented” approach in strengthening the homeodynamic processes of survival and longevity…
Hormetics The science and study of hormesis Hormesis • Biphasic dose response • U-shaped response • Inverted-U shape response • Adaptive response • Compensatory response Three types of dose response curves…
Strengthening the homeodynamics – mild stress-induced HORMESIS A deliberate challenging of the homeodynamic machinery will transiently stimulate compensatory, adaptive, and reparative processes.
Hormesis for healthy ageing. mild “stress of choice” strengthens body’s defensive and reparative processes.
Conditions that bring about hormesis are called: HORMETINS Physical hormetins exercise, heat, stretching, radiation… Nutritional hormetins food restriction, spices, polyphenols, micronutrients… Psychological hormetins mental activity, meditation…
In our labs (since 1998): Improving cellular functionality by hormesis • Ageing and health-span in human cells. (fibroblasts, keratinocytes, endothelial cells, osteoblasts, bone marrow stem cells • Wound healing and migration in human cells. • Differentiation in human cells. (keratinocytes, bone marrow stem cells). • Angiogenesis. (endothelial cells)
Long term hormesis studies on ageing human fibroblasts and keratinocytes, (1998-2009) Mild heat shock 41 ° C, 1 hr, 2-times a week • Slower age-related changes. • Extension of lifespan. • Maintenance of youthful morphology • Improved functionality
Short term hormesis by physical and nutritional hormetins • Improved wound healing by human skin fibroblasts. (heat, glyoxal, curcumin) • Improved differentiation of human keratinocytes (heat, kinetin) • Improved osteoblastic differentiation in telomerase immortalized human bone marrow stem cells. (heat, mechanical stress) • Enhanced angiogenesis by human vascular endothelial cells. (heat)
Hormetins being studied … • Calorie restriction / fasting • Irradiation • Heat • Ethanol • Hypergravity • Hypoxia • Pro-oxidants • Mechanical stress / exercise
Maintaining health and extending the health-span is the driving principle for biogerontology. What is “health” and how to maintain it socially, psychologically, and spiritually? will be discussed in another lecture and a workshop in this congress tomorrow, 21 March 2012. Suresh Rattan, Aarhus University, (sureshrattan.com)
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