Introduction

Although aging is an almost universal truth that we all experience throughout our lives, it is vital that clinicians understand both the clinical and epidemiological relevance of this process. Senescence brings a variety of changes across the spectrum of the body’s systems, which require special care and management. Estimates are that the number of adults older than 65 will reach upwards of 88.5 million by 2050, which will surely place a higher demand for healthcare providers and hospital systems.[1]

While technology has allowed for a massive expansion of the capabilities of modern medical science, many side effects have appeared over time, of which not all have developed at the same rate as medical science in general—not the least of which is our overall prolonged life expectancies. This implies a particular impetus to develop new screening methods, cope with protracted management of disease, which might have proved fatal quite quickly before the advent of certain biomedical technologies, and promote and develop health and wellness lifestyle measures at an early age to avoid the pitfalls of chronic illness and disease later in life.[2]

Issues of Concern

Biologically speaking, aging—or senescence, which more accurately depicts the processes occurring from a biological standpoint—is a chronic, normal culmination of the loss of specific regenerative and bioprotective mechanisms that occur over time in an organism.[3] 

Expanding this idea to the human being, we can begin to ascertain that aging by default necessitates a pro-disease state. This article will attempt to characterize some of the most concerning issues that arise as a result of the normal aging process without, of course, being an entirely exhaustive list of all possible manifestations.

• Organ System: Common medical and surgical issues associated with aging 
• Neurological: Cerebrovascular accident (CVA), Alzheimer disease, and other dementias, Parkinson disease
• Cardiovascular: Coronary artery disease and atherosclerosis, heart failure, hypertension, hematologic malignancy
• Pulmonary: Chronic obstructive pulmonary disease (COPD), lung cancer, pneumonia
• Musculoskeletal: Osteoporosis, osteoarthritis, fractures, skeletal malignancies
• Endocrine: Diabetes mellitus
• Urological/Gynecologic: Urinary tract infections, urogenital cancer, cervical cancers, breast cancers, prostate cancer
• Special Senses: Presbycusis, presbyopia, cataract, macular degeneration, glaucoma
• Gastrointestinal: Malabsorption, GI malignancies, bowel obstruction, diverticular disease
• Other special considerations: Independence, falls, elder abuse and neglect, psychiatric concerns, skin breakdown, skin tears

Cellular Level

At the cellular level, the primary aging-related mechanisms occur as cell proliferation slows eventually to the point of total cessation. Additionally, some literature suggests that increased protein production, apoptotic resistance, and alterations in cellular biochemical activity combined with an accumulation of many like cells in this state, as mentioned above, also contribute to the phenotype we associate with aging. As we age through young and middle adulthood, the overall amount of these senescent cells within our bodies remains relatively low and manageable to overcome by the body’s still higher number of cells, which are not yet senescent and functioning in line with normal physiology.

It is the point at which humans cross the threshold of capacity relative to the number of senescent cells within our body and then their subsequent accumulation in our tissues that they begin to see diseases associated with aging. For instance, some hold that the development of osteoarthritis is associated with accumulations of senescent cells within the affected joint regions, leading to subsequent degeneration and eventually decreased function of that joint and its usefulness in our mobility.[4]

Development

From the moment we enter life, our aging process begins. It is a slow, chronic process, the origins of which are not necessarily well understood but universally accepted. Several theories have emerged as to the origin story of our aging processes. Some hold that aging is a sort of biologically “programmed” mechanism that occurs because extremely advanced age holds little evolutionary benefit, the idea being that if organisms could age for some prolonged-time period, they would be yet another competitor for scarce resources that are also being pursued by a younger generation of organisms mostly thought of as being more capable of reproduction than their aged counterparts.[5] 

By extrapolating this idea of programmed senescence to human beings, it has been proposed that our aging results from genetically pre-programmed hormonal mediation. That is, growth hormone and the insulin pathway, which are well-understood to be associated with development, are controlled by the neuroendocrine system and can play a central role in the mediation of an organism’s aging process via various forms of gene expression and subsequent hormonal fluctuance.

Yet another theory that underpins the development of aging is that of accumulations of damage at the cellular level throughout our lifespan. More specifically, to this point, the suggestion is that the generation of reactive oxygen species and the resulting methylation changes in our DNA could be the underlying mechanism by which we progress into aging.[6] This potential aging mechanism is also closely tied to developing reactive oxygen species, which results in oxidative damage.

Organ Systems Involved

Virtually all organ systems are involved in physiologic changes associated with aging. Cumulatively, the loss of cell turnover, decreased function of mucous membranes, cachexia and skeletal muscle mass wasting, increased atherosclerotic decrease in vascular compliance, and cerebral atrophy eventually all contribute to the variety of changes we see in aging. It is essential to distinguish the normal processes of aging from those pathologic changes that occur in the setting of disease but are markedly more drastic due to the decreased or total loss of compensatory mechanisms.

Specifically, some of the many changes which occur are listed by the organ system below.

Neurological

Abnormal compensatory mechanisms predispose individuals to neurodegeneration and dementia, Parkinson disease, and generalized cerebral atrophy in aging individuals.[7]

Gastrointestinal

Changes in taste and smell, altered gut motility, and intestinal microbiota abnormalities can lead to age-related anorexia and subsequent caloric and/or nutritional deficiency. The weakening of smooth muscle in the intestinal tract can promote the development of diverticular disease and can play a role in bowel obstructions or constipation. Decreased metabolic activity, specifically in the liver, can lead to alterations in drug metabolism.[8]

Renal

Aging leads to a reduced number of functional glomeruli and an increased prevalence of sclerotic changes within the glomeruli or renal vasculature. Additionally, a normal decrease in GFR is observed in advanced age, which places the elderly at much higher risk for complications if they develop chronic or acute kidney disease, as they have less functional glomeruli due to normal aging physiology.[9]

Cardiovascular

Aging lowers the threshold for cardiovascular disease development. This is primarily due to losing cardioprotective and compensatory mechanisms that otherwise help prevent serious cardiac disease development. For example, vascular stiffening, increased left ventricular wall thickness, myocardial fibrosis, calcification of valves and their related structures, as well as decreased aerobic tolerance and increase of problematic cardiomyocyte remodeling, all potentially increase risks for cardiovascular diseases with aging.[10]

Respiratory

Age-related changes in the respiratory system primarily center upon the loss of elasticity and decrease in chest wall compliance, leading to increased work of breathing and residual volume and functional residual capacity. Additionally, decreased strength and function of respiratory muscles are observable. These changes drop an aging patient’s threshold in compensating for an acute illness or respiratory failure.[11]

Endocrine

Age-related decline in endocrine function can yield various effects within the realm of metabolic and hormonal control in aging populations. Thyroxin and triiodothyronine secretion decrease, resulting in overall decreased metabolic activity. Additionally, circadian rhythms become altered, and patients are prone to reduced REM sleep. Alterations in glucose metabolism and insulin secretion develop with age, promoting the development of diabetes mellitus in the elderly. Specific sex-linked endocrine function is impaired or altered with age as well. Women typically experience menopause in their sixth decade of life, accompanied by an increased risk of cardiovascular disease, loss of bone mass, and atrophy of estrogen-responsive tissue.[12]

Function

The aging process is well understood to be part of the natural progression of the human life cycle. By cellular degradation combined with the loss of biosynthetic and cellular repair mechanisms that might have compensated for this degradation in our youth, aging is a chronic and unavoidable state that we will eventually all enter.

Mechanism

On a cellular level, aging is believed to result from a variety of factors related to cellular senescence. The overarching notion is that human cells can only replicate a finite number of times before they become senescent. Previous research has shown that telomeres on the DNA strand gradually shorten as a cell divides.[13] 

The mechanism by which this occurs can be summarized by understanding that the telomeres appear to serve a chromosome-protective role. As the telomere length decreases, so too are the protective qualities of the proteins, which are normally at the distal ends of the telomere and allow DNA repair enzymes to recognize telomeres amongst sites of DNA damage. As a result, the loss of telomere length and concomitant loss of these protective proteins exposes the ends of the chromosomes to damage by DNA repair enzymes.[14] 

This process is compounded by DNA repair complex-mediated activation of transcription factor p53, which, in conjunction with cyclin-dependent kinase inhibitor p21, can result in subsequent senescence of cells and, ultimately, cessation of their metabolic and replicative functions.[15]

Related Testing

Tests relevant to aging and its associated physiology are system and patient or pathology-specific. For example, in an elderly patient with confusion or alterations in neurological status, it might be valuable to administer the mini-mental state examination (MMSE). In contrast, in a 20-year-old patient with similar symptoms, the underlying pathology is likely not due to dementia as it would be in the elderly patient, so different testing would be necessary.[16] Additionally, in patients with advanced age, certain routine screening tools or tests require implementation due to the unique health concerns experienced at older ages. For example, men should receive digital rectal exams for prostate cancer screening, women mammography for breast cancer screening; and annual colonoscopies are excellent screening tools to exclude colon cancer in men and women alike. The purpose of such screening tools is to discover disease as early as possible in its clinical course and identify unhealthy lifestyles and behaviors for which the patient can receive counseling.[17] Such tools are especially valuable in such an aging population as it is well-understood that disease risk increases with age.

Pathophysiology

Three distinct processes can reasonably explain the pathophysiology underlying the aging process:

Production of Free Radicals

Free radicals are well known in the biochemical world as a normal byproduct of healthy physiology in well-regulated, relatively small amounts. They exist as a molecule with a single, unpaired valence electron, rendering them highly reactive in the presence of other substances as they attempt to interact with other substances to obtain additional valence electrons and balance the electron configuration.[18] 

The exact underlying mechanisms underlying the downstream adverse effects of free radical generation and subsequent interaction with cellular components are beyond the scope of this paper, but it bears mentioning that free radicals can denature proteins, destroy membrane lipids, nucleic acids, and certain organelles such as lysosomes and proteasomes.[19] The importance of understanding free radical or reactive oxygen species-derived degenerative changes stems from the belief that accumulated cellular damage via these molecules will—in time—cumulatively overwhelm the cell’s damage repair mechanisms, leading to the eventual physiologic collapse of first, the cell, then the whole organism.[18]

Glycation

Advanced glycosylation end-products form when reactions occur between aldehyde groups of reducing sugars and amino groups of proteins. The formation of these metabolic products occurs in a fashion dependent on elevated blood glucose.[20] In aging individuals, glycemic control becomes less regulated, and glucose tolerance can undergo significant alteration. The predominance of advanced glycosylation end-products can result in abnormalities such as vascular fibrosis, thickened basement membranes, impaired lipid metabolism, and reduced collagenous elasticity. Furthermore, advanced glycosylation end-products are associated with the induction of inflammatory responses, resulting in the release of inflammatory substances and reactive oxygen species, causing further tissue damage.[18]

Reduced Regenerative Capacity

In healthy individuals, a balance exists between one cell’s apoptosis and the maturation and healthy development of another cell that essentially takes the place of the first. Researchers believe that mechanisms within the cell cycle control the programmed death of a senescent cell and also signal externally to other cells the need to develop a new, healthy cell to backfill whatever metabolic demands the senescent cell might have been meeting. The progression between stages in the cell cycle is controlled by regulatory proteins, whose function demonstrably declines in senescent cells compared to younger, healthy cells. The ability of these protein-derived signaling pathways to communicate the need for cell regeneration and maturation in the healthy, young cells seems to be reduced in the aging process, while the pro-apoptotic pathway signaling mechanisms continue to function, leading to a net decline in functional, healthy cells.[18]

Clinical Significance

The aging process is a natural phenomenon that occurs due to a variety of loosely understood mechanisms. Via a combination of telomeric shortening, which triggers pro-apoptotic pathways when sensed in the cell cycle, which subsequently triggers inflammatory mediators and the release of damaging reactive oxygen species, our bodies and their ability to maintain physiologic homeostasis degrade with time. Moreover, so does the body's ability to regenerate or reproduce healthy cells and tissues as we age. The aging process brings phenotypical changes that clinicians must understand and consider when caring for aging patients.

It is essential to recognize that aging involves a great deal of interplay between lifestyle and genetics. An individual who maintains a healthy lifestyle, has access to adequate, routine medical care and screenings, and enters into late adulthood with a clean bill of health will experience a vastly different aging process than someone who is sedentary, makes poor diet and lifestyle choices, and has lived with chronic disease before and upon entry into late adulthood.

Aging is relevant to clinical care and management because it often implies underlying derangements of normal physiology. For example, this article mentioned earlier that urinary tract infections are more common in the elderly. Some patients may experience an increased frequency of falls due to the weakness imposed by their urinary tract infection or their bladder urgency forcing them to attempt to hurriedly make it to a toilet. Clinicians must remain vigilant of the manifestations of disease in aging and, likewise, the presentation of physiologic derangements that pose a potential health risk, like falls and urinary tract infections.[21] Although a normal aspect of typical physiology, aging does incur some manifestations of physiologic derangement that clinicians should learn to interpret in context.