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Aging: Can it be reversed?
Brent C. Williams, MD, MPH
Associate Professor of Medicine
University of Michigan
2
What is Aging?
3
Aging
•is not a disease
•occurs at different rates
•among individuals
•within individuals
•does not generally cause symptoms
4
Characteristics of Aging
• cellular and physiologic deterioration
• increased mortality with age following maturation
• increased vulnerability to disease
• decreased ability to adapt to stress
• impaired homeostasis
“Normal” Aging as:
• Optimal – Best example or idealized
• Usual - most common
• Universal – seen in all humans
• All are influenced by:
• Genetics - Lifestyle
• Physiology - Socioeconomics
5
6
Problems with Normal Aging
• heterogeniety
• normal does not imply without risk
• normal does not imply natural
From Usual to Successful Aging – Clinical
Approach
• Normalizing - Helps patients understand what to expect
• Adjust to likely changes (e.g., sleep/wake, bowels, balance, benign
forgetfulness)
• Identify potential symptoms of disease (sleep apnea, depression;
hypothyroidism; gait disorder; cognitive impairment)
7
Usual to Successful Aging for Clinicians
(cont’d)
• Maintain or improve modifiable causes of age-related change
• Exposures (UV radiation, noise)
• Psychological well-being (social isolation)
• Cognition (mental inactivity)
• Nutrition (cholesterol, sodium, calcium)
• Exercise (fitness, strength, balance)
8
changes in circulating hormone concentrations and hormone
profiles with ageing
Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
Relationship of Age & Hormones
Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
Concentrations of fasting plasma glucose and
plasma glucose after oral glucose administration
over time in non-diabetic individuals.
Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
Conclusion
• The physiological changes occurs in ageing should be considered
when interpreting hormone concentrations in older individuals with
and without endocrine disease.
• The effect of these age-related changes on body composition,
physical function, emotional wellbeing, morbidity, and finally
mortality is only partly known. Some of the changes could be a
beneficial adaptation to ageing, whereas others are not. Future
studies should aim to explore whether endocrine alterations are
maladaptive or adaptive to ageing.
Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
THYROID & AGEING
• Changes in thyroid function tests and physiology are part of aging.
• Using age-specific thyroid stimulating hormone reference ranges may
avoid
unnecessary diagnosis of thyroid disease in elderly population.
• Laboratory results suggesting subclinical thyroid dysfunction may
normalize with time.
• Overt thyroid dysfunction should be treated
• Clinical judgment is needed when deciding on therapeutic options in
elderly population with subclinical thyroid disorders
THYROID AND AGING. Endocrine Practice, 24(4), 369–374.
Epigenetic mechanisms regulating longevity and
aging
The epigenetic hallmarks of senescence and aging
Cell. 2016 August 11; 166(4): 822–839
Regenerative Medicine Approaches for Age-Related Muscle Loss and
Sarcopenia
• The development of new and effective therapies for sarcopenia is
challenging. Potential therapies can target one or more of the
proposed multiple etiologies such as the loss of regenerative capacity
of muscle, age-related changes in the expression of signaling
molecules such as growth hormone, IGF-1, myostatin, and other
endocrine signaling molecules, and age-related changes in muscle
physiology like denervation and mitochondrial dysfunction.
Gerontology 2017;63:580–589
Gerontology 2017;63:580–589
Epigenetic regulation of ageing: linking environmental inputs to
genomic stability
Nat Rev Mol Cell Biol. 2015 October ; 16(10): 593–610
Health relevance of the modification of low grade inflammation in ageing
(inflammageing) and the role of nutrition
• Ageing is characterised by an increase in the concentration of
inflammatory markers in the bloodstream, a phenomenon that has
been termed “inflammageing”.
• Low grade inflammation (LGI) is associated with age-related decline of
many functional systems and with increased risk of ill-health, poor
well-being and mortality.
• Slowing, controlling or reversing LGI is likely to be an important way
to prevent, or reduce the severity of, age-related functional decline
and the onset of conditions affecting health and well-being.
Ageing Res Rev. 2017 Nov;40:95-119
The seven interacting pillars of ageing
Ageing Res Rev. 2017 Nov;40:95-119
Central role of inflammageing in chronic
conditions of ageing
Ageing Res Rev. 2017 Nov;40:95-119
Overview of general mechanisms by which the gut
microbiota affects host intestinal epithelium, immune-
inflammatory response and brain.
Ageing Res Rev. 2017 Nov;40:95-119
Scheme linking diets and specific dietary components to health
and well-being through modulation of gut microbiota and low
grade inflammation (LGI).
Ageing Res Rev. 2017 Nov;40:95-119
Molecular and biological hallmarks of ageing
BJS 2016; 103: e29–e46
Changes in life expectancy throughout history.
Changes in environment, nutrition and medical care
have extended the expected survival age for humans,
with the greatest leaps seen in the latter 200 years
Hallmarks of ageing
BJS 2016; 103: e29–e46
Functional interconnections between the hallmarks of ageing
BJS 2016; 103: e29–e46
Physiological decline and organ dysfunction with age
BJS 2016; 103: e29–e46
Epigenetic modifications, and effect on ageing and
disease
BJS 2016; 103: e29–e46
Mitochondria, metabolic flexibility, and effect of age and disease.
BJS 2016; 103: e29–e46
CONCLUSION
• Understanding the molecular biology of ageing has several potential
clinical implications that may give rise to new ways of managing
surgical disease in the elderly. One would be pharmacological
manipulation to halt, or even reverse, some of the ageing processes,
which may eventually have a positive effect on organ function, organ
recovery or ability to heal after surgery.
• A further understanding of how ageing affects organ systems and
induces dysfunction could lead to methods for reversing or limiting
these effects in the perioperative phase. Furthermore, finding
biomarkers of disease or age dysfunction may replace or support
current use of other investigations, such as cardiac or pulmonary
function/reserve testing.
BJS 2016; 103: e29–e46
Arterial ageing: from endothelial dysfunction to vascular
calcification
Metabolic changes in ageing
J Intern Med 2017 May;281(5):471-482.
Biosynthesis and reaction of nitric oxide (NO), and its biological effects
J Intern Med 2017 May;281(5):471-482
conclusion
• Ageing is the most powerful atherosclerotic risk factor, which explains
why the incidence and prevalence of cardiovascular disease tend to
increase with chronological as well as biological ageing
• The molecular mechanisms underlying arterial ageing could be
putative candidates for targeting by interventions to prevent and slow
the ageing of arteries as a major risk factor for cardiovascular disease
J Intern Med 2017 May;281(5):471-482
THANK YOU

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Aging Reversal: Can It Be Achieved

  • 1. 1 Aging: Can it be reversed? Brent C. Williams, MD, MPH Associate Professor of Medicine University of Michigan
  • 3. 3 Aging •is not a disease •occurs at different rates •among individuals •within individuals •does not generally cause symptoms
  • 4. 4 Characteristics of Aging • cellular and physiologic deterioration • increased mortality with age following maturation • increased vulnerability to disease • decreased ability to adapt to stress • impaired homeostasis
  • 5. “Normal” Aging as: • Optimal – Best example or idealized • Usual - most common • Universal – seen in all humans • All are influenced by: • Genetics - Lifestyle • Physiology - Socioeconomics 5
  • 6. 6 Problems with Normal Aging • heterogeniety • normal does not imply without risk • normal does not imply natural
  • 7. From Usual to Successful Aging – Clinical Approach • Normalizing - Helps patients understand what to expect • Adjust to likely changes (e.g., sleep/wake, bowels, balance, benign forgetfulness) • Identify potential symptoms of disease (sleep apnea, depression; hypothyroidism; gait disorder; cognitive impairment) 7
  • 8. Usual to Successful Aging for Clinicians (cont’d) • Maintain or improve modifiable causes of age-related change • Exposures (UV radiation, noise) • Psychological well-being (social isolation) • Cognition (mental inactivity) • Nutrition (cholesterol, sodium, calcium) • Exercise (fitness, strength, balance) 8
  • 9. changes in circulating hormone concentrations and hormone profiles with ageing Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
  • 10. Relationship of Age & Hormones Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
  • 11. Concentrations of fasting plasma glucose and plasma glucose after oral glucose administration over time in non-diabetic individuals. Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
  • 12. Conclusion • The physiological changes occurs in ageing should be considered when interpreting hormone concentrations in older individuals with and without endocrine disease. • The effect of these age-related changes on body composition, physical function, emotional wellbeing, morbidity, and finally mortality is only partly known. Some of the changes could be a beneficial adaptation to ageing, whereas others are not. Future studies should aim to explore whether endocrine alterations are maladaptive or adaptive to ageing. Lancet Diabetes Endocrinol. 2018 August ; 6(8): 647–658
  • 13. THYROID & AGEING • Changes in thyroid function tests and physiology are part of aging. • Using age-specific thyroid stimulating hormone reference ranges may avoid unnecessary diagnosis of thyroid disease in elderly population. • Laboratory results suggesting subclinical thyroid dysfunction may normalize with time. • Overt thyroid dysfunction should be treated • Clinical judgment is needed when deciding on therapeutic options in elderly population with subclinical thyroid disorders THYROID AND AGING. Endocrine Practice, 24(4), 369–374.
  • 14. Epigenetic mechanisms regulating longevity and aging The epigenetic hallmarks of senescence and aging Cell. 2016 August 11; 166(4): 822–839
  • 15. Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia • The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. Gerontology 2017;63:580–589
  • 17. Epigenetic regulation of ageing: linking environmental inputs to genomic stability Nat Rev Mol Cell Biol. 2015 October ; 16(10): 593–610
  • 18. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition • Ageing is characterised by an increase in the concentration of inflammatory markers in the bloodstream, a phenomenon that has been termed “inflammageing”. • Low grade inflammation (LGI) is associated with age-related decline of many functional systems and with increased risk of ill-health, poor well-being and mortality. • Slowing, controlling or reversing LGI is likely to be an important way to prevent, or reduce the severity of, age-related functional decline and the onset of conditions affecting health and well-being. Ageing Res Rev. 2017 Nov;40:95-119
  • 19. The seven interacting pillars of ageing Ageing Res Rev. 2017 Nov;40:95-119
  • 20. Central role of inflammageing in chronic conditions of ageing Ageing Res Rev. 2017 Nov;40:95-119
  • 21. Overview of general mechanisms by which the gut microbiota affects host intestinal epithelium, immune- inflammatory response and brain. Ageing Res Rev. 2017 Nov;40:95-119
  • 22. Scheme linking diets and specific dietary components to health and well-being through modulation of gut microbiota and low grade inflammation (LGI). Ageing Res Rev. 2017 Nov;40:95-119
  • 23. Molecular and biological hallmarks of ageing BJS 2016; 103: e29–e46 Changes in life expectancy throughout history. Changes in environment, nutrition and medical care have extended the expected survival age for humans, with the greatest leaps seen in the latter 200 years
  • 24. Hallmarks of ageing BJS 2016; 103: e29–e46
  • 25. Functional interconnections between the hallmarks of ageing BJS 2016; 103: e29–e46
  • 26. Physiological decline and organ dysfunction with age BJS 2016; 103: e29–e46
  • 27. Epigenetic modifications, and effect on ageing and disease BJS 2016; 103: e29–e46
  • 28. Mitochondria, metabolic flexibility, and effect of age and disease. BJS 2016; 103: e29–e46
  • 29. CONCLUSION • Understanding the molecular biology of ageing has several potential clinical implications that may give rise to new ways of managing surgical disease in the elderly. One would be pharmacological manipulation to halt, or even reverse, some of the ageing processes, which may eventually have a positive effect on organ function, organ recovery or ability to heal after surgery. • A further understanding of how ageing affects organ systems and induces dysfunction could lead to methods for reversing or limiting these effects in the perioperative phase. Furthermore, finding biomarkers of disease or age dysfunction may replace or support current use of other investigations, such as cardiac or pulmonary function/reserve testing. BJS 2016; 103: e29–e46
  • 30. Arterial ageing: from endothelial dysfunction to vascular calcification Metabolic changes in ageing J Intern Med 2017 May;281(5):471-482.
  • 31. Biosynthesis and reaction of nitric oxide (NO), and its biological effects J Intern Med 2017 May;281(5):471-482
  • 32. conclusion • Ageing is the most powerful atherosclerotic risk factor, which explains why the incidence and prevalence of cardiovascular disease tend to increase with chronological as well as biological ageing • The molecular mechanisms underlying arterial ageing could be putative candidates for targeting by interventions to prevent and slow the ageing of arteries as a major risk factor for cardiovascular disease J Intern Med 2017 May;281(5):471-482

Editor's Notes

  1. Senescence and aging are characterized by (A) loss of histones, (B) imbalance of activating and repressive modifications, (C) transcriptional changes, (D) losses and gains in heterochromatin, (E) breakdown of nuclear lamina, (F) global hypomethylation and focal hypermethylation and (G) chromatin remodeling. These changes are heavily dictated by (H) environmental stimuli (I) and nutrient availability that in turn (J) alter intracellular metabolite concentrations