What are the causes of degenerative diseases in geriatric individuals?

Causes of Degenerative Diseases in Geriatric Individuals

Degenerative diseases in older adults result from a complex interplay of cellular senescence, chronic inflammation, age-related molecular damage, and cumulative decline across multiple physiological systems, with aging itself being the primary risk factor. 1, 2

Primary Biological Mechanisms

Cellular Senescence and Tissue Degeneration

• Cellular senescence is triggered by genomic instability, extreme telomere shortening, metabolic stress, reactive oxygen species, oncogene activation, mitochondrial dysfunction, and epigenetic changes 1
• Senescent cells develop a "senescence-associated secretory phenotype" (SASP), secreting pro-inflammatory cytokines, chemokines, growth factors, and matrix proteases that interfere with tissue repair and regeneration 1
• The accumulation of senescent cells and negative effects of SASP proteins on intercellular matrix and progenitor cells cause tissue degeneration and dysfunction, representing a primary cause of aging and specific age-related degenerative diseases including osteoarthritis, pulmonary fibrosis, atherosclerosis, diabetes, and Alzheimer's disease 1
• Senescent cells become resistant to apoptosis and may persist in tissues for years unless removed by the immune system 1

Hallmarks of Aging as Disease Drivers

The nine biological hallmarks of aging directly contribute to neurodegeneration and other degenerative processes 2:

• Genomic instability from accumulated DNA damage 2
• Telomere attrition leading to cellular dysfunction 2
• Epigenetic alterations that modulate gene expression programs 1, 2
• Loss of proteostasis including protein misfolding 2
• Mitochondrial dysfunction impairing cellular energy metabolism 2
• Cellular senescence as described above 1, 2
• Deregulated nutrient sensing affecting metabolic adaptation 2
• Stem cell exhaustion reducing regenerative capacity 2
• Altered intercellular communication disrupting tissue homeostasis 2

Disease-Specific Pathophysiology

Neurodegenerative Diseases

Aging is the primary risk factor for most neurodegenerative diseases, with one in ten individuals aged ≥65 years having Alzheimer disease, and prevalence continuing to increase with age 2

The causes of most dementias remain elusive, though genetic research has opened frontiers to understanding pathophysiology 1:

• Alzheimer disease accounts for 50-70% of all dementia types 1
• Degenerative forms include Alzheimer disease, dementia with Lewy bodies, Parkinson disease with dementia, and frontotemporal lobar degeneration 1
• Non-degenerative forms include vascular dementia, normal pressure hydrocephalus, and dementia caused by craniocerebral injury, infection, immunity, tumor, poisoning, and metabolic diseases 1

Vascular and Atherosclerotic Diseases

The most common cause of peripheral arterial disease worldwide is atherosclerosis, closely associated with classic risk factors including smoking, diabetes, hypertension, hyperlipidemia, family history, postmenopausal state, and hyperhomocysteinemia 1

Degenerative Structural Disorders

Degenerative disorders lead to loss of structural integrity and subsequent dilation of the arterial wall 1:

• Some progressive arterial degenerative diseases have well-understood pathophysiology (collagen abnormalities in Marfan and Ehlers-Danlos syndromes) 1
• Most degenerative diseases have elusive vascular defects (Erdheim's cystic medial necrosis, arteriomegaly, neurofibromatosis, atherosclerotic aneurysms) 1
• Arterial wall degeneration can lead to aneurysm formation or dissection resulting in arterial rupture or occlusion 1

Musculoskeletal Degeneration

As a consequence of acute and/or chronic disease in combination with age-related degenerative changes, limitations in physical, mental, and social functions occur 1:

• Sarcopenia is characterized by disproportionate loss of muscle mass and strength accompanied by decline in physical activity, functionality, and performance 1
• Excessive muscle loss results in physical impairment, frailty, disability, and dependence on others 1
• Sarcopenia impairs metabolic adaptation to stress and disease 1

Joint Diseases

Inflammation, both locally and systemically, promotes damage to joints and bones as well as joint-related functional deficits 3:

• Cross-talk between cartilage and subchondral bone—and loss of balance between these structures—is a critical element in joint disease pathogenesis 3
• Dysregulation of mast cells is associated with alterations of junction structures (cartilage, bone, synovia, matrix, nerve endings, blood vessels) 3
• Persistent mast cell activation facilitates spinal neuroinflammation through interaction with microglia 3

Systemic Contributing Factors

Frailty and Multisystem Decline

Frailty represents a distinct clinical syndrome characterized by increased vulnerability to stress as a consequence of cumulative decline in many physiological systems during aging, affecting approximately 25% of persons aged 85 years or older 1

Reduced Adaptive Capacity

A reduced adaptive and regenerative capacity characterizes older patients, making it more difficult to return the patient to an unrestricted or previous condition 1

Nutritional and Metabolic Factors

Inadequate nutrition contributes to disease progression and is regarded as one important contributing factor in the complex etiology of sarcopenia and frailty 1

Common Pitfalls in Understanding Causation

• Do not assume single-cause etiology: Degenerative diseases result from multiple interacting mechanisms rather than isolated pathways 1, 2
• Recognize that cellular senescence burden increases with aging in multiple tissues (CD4+ lymphocytes, kidney epithelia, skin), but quantification is complex because heterogeneous forms develop according to different triggers and tissues 1
• Understand that none of the characteristic biomarkers (p53, p21, senescence-associated β-galactosidase, SASP factors) are specific to senescence, and p16Ink4a is not always present 1
• Appreciate that systemic pathophysiological processes are diverse and include atherosclerosis, degenerative diseases, dysplastic disorders, vascular inflammation, and both in situ thrombosis and thromboembolism 1