Malaysian Healthy Ageing Society Healthy Ageing from molecules to - - PowerPoint PPT Presentation

Organised by:

Malaysian Healthy Ageing Society

Co-Sponsored:

Suresh Rattan, PhD, DSc

Editor-in-Chief, Biogerontology Department of Molecular Biology and Genetics Aarhus University, Denmark

Healthy Ageing

from molecules to hormesis

Aarhus University - library Aarhus University – science park Biogerontology, class Molecular Biology Dept

Biological basis of ageing and longevity

Psychological modulators Sociological effectors and implications

• When ageing occurs in life, and why?
• What happens during ageing?
• What is the molecular basis of ageing?
• How to intervene….

Ageing from a biological perspective….

Lifespan of an individual is limited...

Average LS 30-40 days 20-24 months 75-80 years Maximum LS 80 days 36 months 122 years Examples Fruitflies Rats/mice Humans

Types of lifespan

Besse Cooper – 26 Aug. 1896

1. 2.

Average Lifespan of a cohort / population Maximum Lifespan – within a cohort

Humans

Essential Lifespan

(ELS)

Species Lifespan required in evolutionary terms

40 - 45 years

Three types of lifespan

3.

If an organism lives beyond essential lifespan of its species, that is when ageing sets in - biologically

My own growth, maturation, immortality, & ageing....

1979-1984 2005 2007 Growth-maturation Looking forward to..., 2041 My route to immortality – Anuresh 2011

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

We are not programmed to age and die. There are no gerontogenes whose sole function is to cause ageing and eventual death.

Programmed to age and die?

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, aldehydes

Biochemical infidelity

errors, modifications, misfolding

• Genomic stability
• Epigenomic stability
• Protein stability
• Macromolecular turnover
• Free radical counteraction

Sources of damage Maintenance and repair systems

Vulnerability zone Homeodynamic space

Growth, development and maturation….

Maintenance and repair systems create homeodynamic space

Biological characteristics of the homeodynamic space

• 1. Stress response and buffering capacity
• 2. Damage prevention, repair and removal
• 3. Continuous remodelling and adaptation

• 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

Age-related changes have been well described…

Ageing of cells in culture

Sparse culture Confluent culture

young: less than 30% lifespan completed middle aged: between 60 and 80% lifespan completed

• ld: more than 95% lifespan completed

The Hayflick system

with Len Hayflick - Warsaw, Oct. 2007

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

Ageing occurs at all levels of biological

• rganisation, but differently…

Ageing is the shrinkage of the homeodynamic space

Homeodynamic space

Vulnerability zone

Homeodynamic space

Vulnerability zone

Cancer Alzheimer’s Parkinson’s Sarcopenia Cardiovascular problems Diabetes Osteoporosis Cataract

Ageing is the common factor for several diseases

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.

Better material organs Partial or complete serial replacement.

Piecemeal remedies

Stem cell therapies

A formula for eternal youth

E = G M C2

G Genes and gene-networks Intelligent Re-designing...!!!

Creating new parts?

• 1. to repair molecular damage
• 1. to remove molecular damage
• 2. to neutralise damaging agents

Drugs and nutriceuticals

• Vitamins
• Hormones
• Bio-extracts/spices
• Natural and synthetic antioxidants

Improving M = milieu in which genes operate

M in E = G M C2

Cosmetics and cosmeceuticals Milieu is…..

• intra-cellular
• inter-cellular
• systemic
• body level
• psychological level
• group level
• population level
• global
• universal ?????

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…

A major shift in approach towards ageing interventions….

Three types of dose response curves…

Hormetics

The science and study of hormesis

Hormesis

• Biphasic dose response
• U-shaped response
• Inverted-U shape response
• Adaptive response
• Compensatory response

A deliberate challenging of the homeodynamic machinery

will transiently

stimulate compensatory, adaptive, and reparative processes.

Strengthening the homeodynamics –

mild stress-induced HORMESIS

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)

Mild heat shock 41°C, 1 hr, 2-times a week

• Slower age-related changes.
• Extension of lifespan.
• Maintenance of youthful morphology
• Improved functionality

Long term hormesis studies on ageing human fibroblasts and keratinocytes, (1998-2009)

• 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) Short term hormesis by physical and nutritional hormetins

Hormetins being studied…

• Calorie restriction / fasting
• Irradiation
• Heat
• Ethanol
• Hypergravity
• Hypoxia
• Pro-oxidants
• Mechanical stress /

exercise

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)

Maintaining health and extending the health-span is the driving principle for biogerontology.