THE CHEMISTRY OF AGEING
Padmamalika Hazra
Msc.,Ph.D(Organic
Chemistry).,D.Phil(Medical Biochemistry)
Dept of Chemistry, St.John’s College,Agra
Holy Grail of Immortality
• 'I believe in 25 years we could see the creation of the first
products that can postpone human aging significantly. This
would only be the beginning of a long process of
technological development in which human life span would
be aggressively extended. The only practical limit to human
life span is the limit of human technology'
• Michael Rose, University of California, Irvine in Rose M.R.
and Nusbaum TJ (1994). Prospects for postponing human
aging FASEB Journal,8,925-8.1
• 'I wish to believe in immortality-I wish to live with you
forever"
• Letter of John Keats, Physician and Poet, to his beloved,
Fanny Brawne
Adding Life to Years not merely Years
to Life
• Man’s quest for the Holy Grail of Immortality
• Conviction that Future Technology can achieve
this
• Search of the Ancient Alchemists for the Elixir of
Life
• Theories of Ageing revolve around Chemical
Mechanisms
• Tangible progress in extending Life ie Adding Life
to Years, and Years to Life, can only be achieved
by measuring Chemical biomarkers of Ageing
The Quantification of Ageing
• Biomarkers that can be measured chemically
allow the quantification of Ageing.
• Why is quantification important?
• “Core of Scientific Advance is Measurement”
•
LORD KELVIN,19th century
• “To measure is to know…”
• “If you cannot measure it, you cannot improve
it”
LORD KELVIN’s MAXIM
• "In physical science the first essential step in the
direction of learning any subject is to find principles of
numerical reckoning and practicable methods for
measuring some quality connected with it. I often say
that when you can measure what you are speaking
about, and express it in numbers, you know something
about it; but when you cannot measure it, when you
cannot express it in numbers, your knowledge is of a
meagre and unsatisfactory kind; it may be the
beginning of knowledge, but you have scarcely in your
thoughts advanced to the state of Science, whatever
the matter may be." [PLA, vol. 1, "Electrical Units of
Measurement", 1883-05-03]
Chemical Mechanisms of Ageing
• Protein cross linking
• The stiffness of the elderly is in large measure
due to cross linking of collagen molecules
• Skin wrinkling
• Stiffness of the arteries and of the lungs
• Glycation of molecules also contributes to
crosslinking: Diabetes a form of acclerated ageing
• Oxidative Stress:Marked b y rise in free radicals,
and depletion of free radical sinks!
Current Theories of Ageing
•
•
•
•
Dystopic Immune Function
Neuro Endocrine changes
Free Radicals and Oxidative Stress
Cell ageing Theory: Telomere shortening
imposes the Hayflick limit on the number of
times that cells can divide
• Somatic Cell mutation
• Mitochondrial DNA mutation
The havoc that Free Radicals cause!
• Free radicals are highly reactive
• Cause oxidative alteration in collagen, elastin
and DNA;
• Changes of mitochondrial membrane
• Fibrosis of arterioles and capillaries secondary
to vessel injury.
OXIDATIVE STRESS MARKERS:Classes
• Molecules that are modified by interactions with
ROS in the microenvironment;
• Molecules of the antioxidant system that change
in response to increased redox stress.
• DNA, lipids (including phospholipids), proteins
and carbohydrates are examples of molecules
that can be modified by excessive ROS in vivo.
• . Some of these known to have direct effects on
function of the molecule (e.g. inhibit enzyme
function), but others merely reflect the degree of
oxidative stress in the local environment. T
IMPORTANT KEY MOLECULES
MEASURED
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ROS, reactive oxygen species;
IsoP, isoprostane;
MDA,malondialdehyde;
TBARS, thiobarbituric acid reacting substance;
O2−, superoxide;
OH, hydroxyl radical;
HO2, hydroperoxyl radical;
ONOO−, peroxynitrite;
HOCl,hypochlorous acid;
H2O2, hydrogen peroxide;
NO2, nitrogen dioxide;
MPO,myeloperoxidase;
OxLDL, Oxidized low-density lipoprotein;
GSH, glutathione (reduced)
HORMONAL MARKERS
•
•
•
•
•
•
•
•
•
DHEA-S:Dehydroxyepiandrosterone Sulphate
Plasma Noradrenaline
.Melatonin
.Serotonin
17 ketosteroid/ hydroxyketosteroid ratios
Serum cortisol and the ratio of this to DHEA-S
Pregnenolones
Thyroxine binding globulin
NON HORMONAL MARKERS
•
•
•
•
•
•
•
•
•
•
•
•
Prostate Specific antigen
Ascorbic acid
Fibrinogen
Serum and Urinary Creatinine.
Zinc
Haemoglobin A1 C (HbA1C), also called glycated haemoglobin
Blood Urea/Urea Nitrogen
Low density Lipoprotein Cholesterol.
Serum albumin/globulin ratio
Serum alkaline phosphatase
C-reactive protein
Urinary albumin levels.
Using these biomarkers
• Each of these can be measured serially over a
period of time
• Measuring natural ageing
• Comparing ageing rates
• Determining the effect of interventions using,
for example, antioxidants or other agentsmicronutrients, 0mega 3 unsaturated acids
etc .
Is Quantification of Ageing possible in
Man?
A 2015 report from the University of Otago ,New
Zealand about a longitudinal study by Prof Richie
Poulton on over 1000 subjects cohort born in
1972-3. ( PNAS of July 6,2015 )
A panel of 18 biomarkers were studied.
When the 18 measures were assessed together in
the study members at age 38, they were able to set
‘biological ages’ for each person.
In contrast to their chronological ages, these
ranged from under 30 to nearly 60 years.
Determining the Pace of Ageing
• The researchers then went back to look at the
individuals’ same measures at age 26 and 32.
• After drawing a slope for each variable, the
team added the18 slopes for each member to
determine that individual’s hidden pace of
aging while they were still young on the
outside.
The Otago Study: RESULTS
• Most subjects were found to be clustered
around one biological year per chronological
year,
• Others were found to be aging as fast as three
biological years per actual year.
• Many were aging at zero years per year; they
were staying younger than their age.
Physical Correlates of these markers
•
•
•
•
•
Individuals who were aging more rapidly were
Less physically able
Showed cognitive decline and brain aging
Reported worse health
Looked older. ( The latter was based on Duke
University students’ judgement of relative age
based on study members’ facial photographs)
The Future
• Being able to detect accelerated aging at an
early stage paves the way for applying
therapies that slow aging and lessen agerelated ailment,
• The study of chemical markers is thus of
abiding importance.
BACK UP SLIDES
SOURCES OF FREE RADICALS
• Toxic byproducts of normal aerobic cell
metabolism
• Parts of molecules with extra or missing
electrons that makes them highly charged and
reactive
• Also obtained through diet and environment –
tobacco
smoke,pollution,sunlight,radiation,nitrites
used in food preservation, or in smoked meats
What is DHEAS
• Dehydroepiandrosterone (DHEA) is the major steroid
produced by the adrenal zona reticularis and, in contrast to
cortisol and aldosterone, its secretion declines with ageing.
• DHEA exhibits its action mainly by conversion to sex
steroids. In addition, DHEA has neurosteroidal properties
and may exhibit direct action via specific binding sites on
endothelial cells.
• Beneficial effects of DHEA in patients with adrenal
insufficiency and future research will hopefully elucidate its
role in patients receiving pharmacological glucocorticoid
treatment.
• In addition, potentially adverse effects on sex steroiddependent tumour growth need to be considered.
DHEAS, PNAS,Balieau et al. 2000 Apr
11; 97(8): 4279–4284.
• De hydroxy epi androstene dionelevels decrease profoundly
with age, and the question is posed whether administration of
the steroid to compensate for the decline counteracts defects
associated with aging. .
• 280 subjects were given DHEA, 50 mg, or placebo, orally, daily
for a year in a double-blind, placebo-controlled study.. Besides
the reestablishment of a “young” concentration of DHEAS, a
small increase of testosterone and estradiol was noted,
particularly in women,
• Bone turnover improved selectively in women >70 years old,
A significant increase in libido
• Improvement of the skin status was observed, particularly in
women, in terms of hydration, epidermal thickness, sebum
production, and pigmentation.
doping).
Melatonin
•
•
•
•
•
•
Made by the pineal gland
Strong antioxidant-mops up free radicals
Also involved in Sleep /Wake cycles
Used to treat Jet lag
Possible role in preventing Cancers
Used to treat insomnia
Other antioxidants
• Vitamin C
• Vitamin A
• Vitamin E- tocopherol and toco-trienol
congeners
• Selenium