Ageing and Disease: A Comprehensive Overview

AGING & DISEASE

Introduction to Aging

Biological aging, termed senescence (process of ageing), is one of the most complex biological processes.

Geriatric – coined by Dr. Ignatz Nascher

Geriatrics is often used as a generic term relating to older adults, but speci­cally refers to the medical care of the older adults. Geriatricians are physicians trained in geriatric medicine.

Scope of practice: older adults from 65 until death.

• - Aging is an irreversible, gradual process marked by declining tissue and cell functions, increasing the risk of diseases like neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system disorders.

• Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility.

• Aging is defined as the progressive accumulation of damage over time, leading to disturbed function on the cellular, tissue and organ level and eventually to disease and death. It is a multifactorial process where genetic, endogenous and environmental factors play a role.

• Aging is a gradual and irreversible pathophysiological process. It is associated with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. 

• Aging is a ubiquitous biological process that results in a progressive and irreversible decline in physical function across all organ systems that is induced by the accumulation of damage in response to a variety of stressors.

Aging has been associated with a loss of complexity in a wide range of physiological processes and anatomic structures. Many evolutionary biologists would deny that aging is part of the genetic repertoire (prepared to perform) of an animal. Rather, they would consider aging to be the default state occurring after the animal has fulfilled the requirements of natural selection.

After its offspring are born and raised, the animal can die. Indeed, in many organisms, from moths to salmon, this is exactly what happens. As soon as the eggs are fertilized and laid, the adults die.

Disease, any harmful deviation from the normal structural or functional state of an organism, generally associated with certain signs and symptoms and differing in nature from physical injury. A diseased organism commonly exhibits signs or symptoms indicative of its abnormal state. Thus, the normal condition of an organism must be understood in order to recognize the hallmarks of disease. Nevertheless, a sharp demarcation between disease and health is not always apparent.

Although the development of modern medicine has promoted human health and greatly extended life expectancy, with the aging of society, a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals. 

Current research on aging focuses on elucidating how various endogenous and exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and deregulated nutrient sensing) participate in regulating aging. 

Furthermore, thorough research on the pathogenesis of aging to identify interventions that promote health and longevity (such as caloric restriction, microbiota transplantation, and nutritional intervention) and clinical treatment methods for aging-related diseases (depletion of senescent cells, stem cell therapy, antioxidative and anti-inflammatory treatments, and hormone replacement therapy) could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.

The Nine Hallmarks of Ageing

These biological hallmarks define the ageing process and its impact on health:

• Genomic Instability: Accumulation of DNA damage over time.

• Telomere Attrition: Shortened telomeres lead to impaired cell division.

• Epigenetic Alterations: Changes in gene expression patterns over time.

• Loss of Proteostasis: A decline in protein quality control mechanisms.

• Deregulated Nutrient Sensing: Disrupted metabolic pathways.

• Mitochondrial Dysfunction: Impaired energy production in cells.

• Cellular Senescence: Accumulation of senescent cells contributes to tissue dysfunction.

• Stem Cell Exhaustion: Reduced capacity for tissue regeneration.

• Altered Intercellular Communication: Disrupted signaling between cells.

Molecular Mechanisms of Aging

1. Genomic Instability

   • DNA damage accumulates with age, leading to cellular senescence.

   • Mitochondrial DNA (mtDNA) mutations and nuclear architecture changes (e.g., lamin deficiencies) contribute to aging.

2. Telomere Dysfunction

   • Telomeres shorten with cell division, triggering DNA damage responses and senescence.

   • Telomerase activity declines with age but is reactivated in some cells to mitigate aging effects.

3. Epigenetic Alterations

   • Changes in DNA methylation, histone modifications, and chromatin remodeling affect gene expression and aging.

   • Epigenetic clocks (e.g., Horvath’s clock) predict biological age and disease risk.

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4. Loss of Proteostasis

   • Misfolded proteins accumulate due to impaired degradation systems (ubiquitin-proteasome, autophagy).

   • Chaperones and heat shock proteins help maintain protein balance but decline with age.

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5. Mitochondrial Dysfunction

   • Reactive oxygen species (ROS) from mitochondria damage cellular components.

   • Impaired mitophagy and energy metabolism (e.g., NAD+ decline) accelerate aging.

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6. Cellular Senescence

   • Senescent cells secrete pro-inflammatory factors (SASP), damaging neighboring cells and tissues.

   • Clearance of senescent cells alleviates age-related diseases in animal models.

7. Stem Cell Exhaustion

   • Stem cell function declines with age due to reduced autophagy and asymmetric division.

   • MSC transplantation shows promise for regenerative therapies.

8. Altered Intercellular Communication

   • Senescent cells disrupt tissue microenvironments via SASP and extracellular vesicles (EVs).

9. Deregulated Nutrient Sensing

   • Pathways like insulin/IGF-1, mTOR, and AMPK influence aging.

   • Gut microbiota (gut-brain axis) plays a role in metabolic and inflammatory aging.

Aging-Related Diseases and Mechanisms

1. Neurodegenerative Diseases (Alzheimer’s, Parkinson’s)

   • Protein aggregates (Aβ, tau, α-synuclein), mitochondrial dysfunction, and neuroinflammation drive pathology.

2. Cardiovascular Diseases (Heart Failure, Atherosclerosis)

   • Senescent cardiomyocytes and endothelial cells promote inflammation and fibrosis.

   • Oxidative stress and epigenetic changes impair vascular function.

3. Metabolic Diseases (T2DM, NAFLD)

   • β-cell senescence and insulin resistance are key in diabetes.

   • NAFLD progression involves mitochondrial dysfunction, ER stress, and gut microbiota dysbiosis.

4. Musculoskeletal Diseases (Osteoarthritis, Osteoporosis)

   • Senescent chondrocytes and osteoblasts disrupt joint/bone homeostasis.

   • Oxidative stress and stem cell exhaustion impair tissue repair.

5. Other Diseases (COPD, AMD, Presbycusis, Cancer)

   • COPD: Lung cell senescence and mitochondrial damage.

   • AMD: Retinal cell senescence and oxidative stress.

   • Cancer: Senescence can both suppress and promote tumorigenesis via SASP.

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Interventions and Treatments

1. Lifestyle Interventions

   • Mediterranean diet, caloric restriction, and exercise reduce disease risk.

2. Pharmacological Approaches

   • Senolytics (e.g., dasatinib + quercetin): Remove senescent cells.

   • Senomorphics (e.g., metformin, rapamycin): Suppress SASP.

   • Antioxidants (e.g., NAD+ boosters): Mitigate oxidative stress.

3. Advanced Therapies

   • Stem cell transplantation (e.g., MSCs for bone/cartilage repair).

   • Gene therapy (e.g., telomerase activation).

   • Microbiome modulation (e.g., probiotics, FMT).

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   • 1. Major Age-Related Diseases

   • These diseases are closely tied to ageing processes:

     • Cardiovascular Diseases: High prevalence due to blood vessel deterioration.

     • Neurodegenerative Diseases: Conditions like Alzheimer’s and Parkinson’s.

     • Cancer: Increased risk due to mutations and weakened immune surveillance.

     • Osteoarthritis and Type 2 Diabetes: Common chronic conditions in ageing populations.

     2. Cellular Senescence and Chronic Inflammation

     • Senescence: Accumulated senescent cells (with SASP) promote inflammation and tissue dysfunction.

     • Inflammation: Chronic, low-grade inflammation linked to diseases like cardiovascular disorders, diabetes, and neurodegeneration.

     3. Genetic and Environmental Factors

     • Genetics: Certain genetic predispositions (e.g., APOE4 for Alzheimer’s) increase disease risk.

     • Environment: Lifestyle factors, such as diet, stress, and pollution, influence ageing outcomes.

     • Gene-Environment Interactions: These complex interactions shape individual health trajectories.

     4. Interventions for Healthy Ageing

     Strategies to enhance lifespan and healthspan:

     • Caloric Restriction: Proven to extend lifespan in model organisms.

     • Exercise: Improves both physical and cognitive health.

     • Medication: Compounds like metformin, rapamycin, and senolytics show promise.

     • Lifestyle Modifications: A Healthy diet, stress management, and quitting smoking are critical.

     5. Future Directions

     • Targeted Therapies: Develop new treatments for age-related diseases.

     • Personalized Interventions: Tailor strategies to individual needs.

     • Promoting Healthy Ageing: Enhance healthspan and overall quality of life through ongoing research.

Challenges and Future Directions

• Heterogeneity: Aging mechanisms vary by tissue and individual.

• Side Effects: Anti-aging drugs (e.g., metformin) may have adverse effects at high doses.

• Integration: Combining genomics, proteomics, and AI may refine personalized interventions.

Conclusion

Understanding aging’s molecular and cellular basis offers avenues to delay age-related diseases. While challenges remain, advances in senolytics, stem cells, and nutrient-sensing modulators hold promise for extending healthspan. Future research should focus on translating preclinical findings into safe, effective clinical therapies.

Ageing and health

Key facts

• All countries face major challenges to ensure that their health and social systems are ready to make the most of this demographic shift.
• In 2050, 80% of older people will be living in low- and middle-income countries.
• The pace of population ageing is much faster than in the past.
• In 2020, the number of people aged 60 years and older outnumbered children younger than 5 years.
• Between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22%.

Overview

People worldwide are living longer. Today most people can expect to live into their sixties and beyond. Every country in the world is experiencing growth in both the size and the proportion of older persons in the population.

By 2030, 1 in 6 people in the world will be aged 60 years or over. At this time the share of the population aged 60 years and over will increase from 1 billion in 2020 to 1.4 billion. By 2050, the world’s population of people aged 60 years and older will double (2.1 billion). The number of persons aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million.

While this shift in distribution of a country's population towards older ages – known as population ageing – started in high-income countries (for example in Japan 30% of the population is already over 60 years old), it is now low- and middle-income countries that are experiencing the greatest change. By 2050, two-thirds of the world’s population over 60 years will live in low- and middle-income countries.

Ageing explained

At the biological level, ageing results from the impact of the accumulation of a wide variety of molecular and cellular damage over time. This leads to a gradual decrease in physical and mental capacity, a growing risk of disease and ultimately death. These changes are neither linear nor consistent, and they are only loosely associated with a person’s age in years. The diversity seen in older age is not random. Beyond biological changes, ageing is often associated with other life transitions such as retirement, relocation to more appropriate housing and the death of friends and partners.

Common health conditions associated with ageing

Common conditions in older age include hearing loss, cataracts and refractive errors, back and neck pain and osteoarthritis, chronic obstructive pulmonary disease, diabetes, depression and dementia. As people age, they are more likely to experience several conditions at the same time.

Older age is also characterized by the emergence of several complex health states commonly called geriatric syndromes. They are often the consequence of multiple underlying factors and include frailty, urinary incontinence, falls, delirium and pressure ulcers.

Factors influencing healthy ageing

A longer life brings with it opportunities, not only for older people and their families, but also for societies as a whole. Additional years provide the chance to pursue new activities such as further education, a new career or a long-neglected passion. Older people also contribute in many ways to their families and communities. Yet the extent of these opportunities and contributions depends heavily on one factor: health.

Evidence suggests that the proportion of life in good health has remained broadly constant, implying that the additional years are in poor health. If people can experience these extra years of life in good health and if they live in a supportive environment, their ability to do the things they value will be little different from that of a younger person. If these added years are dominated by declines in physical and mental capacity, the implications for older people and for society are more negative.

Although some of the variations in older people’s health are genetic, most is due to people’s physical and social environments – including their homes, neighbourhoods, and communities, as well as their personal characteristics – such as their sex, ethnicity, or socioeconomic status. The environments that people live in as children – or even as developing fetuses – combined with their personal characteristics, have long-term effects on how they age.

Physical and social environments can affect health directly or through barriers or incentives that affect opportunities, decisions and health behaviour. Maintaining healthy behaviours throughout life, particularly eating a balanced diet, engaging in regular physical activity and refraining from tobacco use, all contribute to reducing the risk of non-communicable diseases, improving physical and mental capacity and delaying care dependency.

Supportive physical and social environments also enable people to do what is important to them, despite losses in capacity. The availability of safe and accessible public buildings and transport, and places that are easy to walk around, are examples of supportive environments. In developing a public-health response to ageing, it is important not just to consider individual and environmental approaches that ameliorate the losses associated with older age, but also those that may reinforce recovery, adaptation and psychosocial growth.

Challenges in responding to population ageing

There is no typical older person. Some 80-year-olds have physical and mental capacities similar to many 30-year-olds. Other people experience significant declines in capacities at much younger ages. A comprehensive public health response must address this wide range of older people’s experiences and needs.

The diversity seen in older age is not random. A large part arises from people’s physical and social environments and the impact of these environments on their opportunities and health behaviour. The relationship we have with our environments is skewed by personal characteristics such as the family we were born into, our sex and our ethnicity, leading to inequalities in health.

Older people are often assumed to be frail or dependent and a burden to society. Public health professionals, and society as a whole, need to address these and other ageist attitudes, which can lead to discrimination, affect the way policies are developed and the opportunities older people have to experience healthy aging.

Globalization, technological developments (e.g., in transport and communication), urbanization, migration and changing gender norms are influencing the lives of older people in direct and indirect ways. A public health response must take stock of these current and projected trends and frame policies accordingly.

WHO response

The United Nations (UN) General Assembly declared 2021–2030 the UN Decade of Healthy Ageing and asked WHO to lead the implementation. The UN Decade of Healthy Ageing is a global collaboration bringing together governments, civil society, international agencies, professionals, academia, the media and the private sector for 10 years of concerted, catalytic and collaborative action to foster longer and healthier lives.

The Decade builds on the WHO Global Strategy and Action Plan and the United Nations Madrid International Plan of Action on Ageing and supports the realization of the United Nations Agenda 2030 on Sustainable Development and the Sustainable Development Goals.

The UN Decade of Healthy Ageing (2021–2030) seeks to reduce health inequities and improve the lives of older people, their families and communities through collective action in four areas: changing how we think, feel and act towards age and ageism; developing communities in ways that foster the abilities of older people; delivering person-centred integrated care and primary health services responsive to older people; and providing older people who need it with access to quality long-term care.

Introduction to Geriatric Care

1. Define geriatric care and explain its significance in modern healthcare.

Geriatric care is a specialized branch of medicine and healthcare focused on addressing the unique physical, mental, emotional, and social needs of elderly individuals, typically those aged 65 and above. It emphasizes preventive care, chronic disease management, functional independence, and improving quality of life.

Significance in Modern Healthcare:

• Aging Population: With increasing life expectancy, the elderly population is growing, necessitating specialized care.

• Complex Health Needs: Older adults often have multiple chronic conditions (e.g., diabetes, arthritis, dementia) requiring coordinated care.

• Functional Decline: Geriatric care helps maintain mobility, cognition, and independence.

• Preventive Approach: Reduces hospitalizations through early intervention and personalized care plans.

• Psychosocial Support: Addresses mental health issues like depression and social isolation common in aging.

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2. Discuss three major challenges faced by elderly individuals in daily living.

1. Chronic Health Conditions:

   • Many elderly individuals suffer from multiple chronic diseases (e.g., hypertension, arthritis, heart disease), leading to pain, fatigue, and reduced mobility.

   • Managing medications and frequent doctor visits can be overwhelming.

2. Mobility and Physical Limitations:

   • Age-related muscle loss (sarcopenia), joint pain, and balance issues increase the risk of falls and fractures.

   • Difficulty performing daily activities (e.g., bathing, dressing, cooking) without assistance.

3. Cognitive Decline and Mental Health Issues:

   • Conditions like dementia and Alzheimer’s impair memory and decision-making.

   • Social isolation, grief, and depression are common due to loss of loved ones or reduced social interaction.

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3. Compare and contrast geriatric care with general adult healthcare.

Aspect	Geriatric Care	General Adult Healthcare
Focus	Holistic care for aging-related issues (physical, cognitive, social).	Broad care for adults (18-64), often disease-specific.
Patient Population	Primarily adults 65+ with multiple chronic conditions.	Adults of all ages, usually with acute or single chronic conditions.
Approach	Multidisciplinary (doctors, nurses, therapists, social workers).	Often single-provider or specialist-driven.
Goals	Maintain independence, manage chronic diseases, improve quality of life.	Treat illnesses, prevent disease, promote wellness.
Common Issues Addressed	Dementia, falls, polypharmacy, frailty, end-of-life care.	Infections, injuries, chronic diseases (e.g., diabetes, hypertension).
Preventive Measures	Fall prevention, cognitive screenings, caregiver support.	Routine check-ups, vaccinations, lifestyle counseling.

Key Differences:

• Geriatric care is more patient-centered and focuses on functional ability rather than just treating diseases.

• It involves more coordination among specialists due to complex health needs.

• End-of-life care and ethical decision-making (e.g., advanced directives) are more prominent in geriatrics.

By understanding these distinctions, healthcare providers can deliver more effective, compassionate care tailored to elderly patients' needs.