THE CHEMISTRY OF AGEING

Padmamalika HazraMsc.,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 agents- micronutrients, 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 age-related 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 steroid-dependent 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