Aging & Age-Related Diseases

Aging can range from “successful” to “pathological”, depending on the reserve functions of the different physiological systems, their resilience, and the consequent appearance of disease.

Guillermo Caletti, MD, PhD

Aging Aging is a complex phenomenon which, on its various levels —molecular, cellular, physiological and psycho-social, etc.— proves difficult to define (1).

The definition of aging is difficult, and remains under discussion due to the undetermined factors causing this complex phenomenon. The most accepted functional definition is that a decrease in physiological reserves, while still supporting acceptable functioning in the steady state, cannot adapt to any additional stress, even if it is psychological in nature. Aging itself is thus associated with progressive homeostatic/homeodynamic dysregulation that causes the organism to progressively lose resilience, until it becomes completely non-resilient (Yates 2002; Lipsitz 2004).

Aging can range from “successful” to “pathological”, depending on the reserve functions of the different physiological systems, their resilience, and the consequent appearance of disease. Frailty can be considered an intermediate, yet distinct state between these two extremes, where a certain possibility for reversal of pathological processes may still exist (Bortz, 2002).

The development of longevity drugs has evolved from a far-off goal into an industry priority. Several companies are working on developing drugs that target aging, and some of these drugs are currently in clinical trials.

Frailty may thus set off a chain of events that result in a pathological situation, or disease, in a formerly-healthy aging person. This occurs when there is no other reason available to explain the cause for a decline in health. The ability to predict frailty is key to its modulation and prevention.

The best-known aspect of frailty is its consequences, which include morbidity, institutionalization and ultimately, death.

Impaired nutritional status – primarily related to poor nutrient intake – is also one of the key characteristics in frailty. Most frail patients experience fatigue, problems with balance, decreased endurance and difficulties adapting to changing circumstances (Pel-Little et al. 2009; De Lepeleire et al. 2009).

Not all frail elderly people will experience all the symptoms mentioned. This seems to be closely associated with remaining reserve capacity, and hence, with resilience. Only when this reserve capacity of interconnected physiological systems is reduced to a crucial level, will the signs and symptoms of frailty become clinically evident. This is the moment when the aging process may cause a clinically apparent disease entity, namely frailty. Reserve capacity is decreased and the adaptation mechanisms to stressors can no longer be mobilized, leading to a breakdown of homeostasis and crossing the threshold to clinically manifested frailty syndrome.

inflAmm-Aging Inflammation is a physiological process that repairs tissues in response to endogenous or exogenous aggressions. A chronic state of inflammation may have detrimental consequences. Aging is associated with increased levels of circulating cytokines and proinflammatory markers. Age-related changes in the immune system – known as immunosenescence – and increased secretion of cytokines by adipose tissue represent the major causes of chronic inflammation (M. Michaud et al. 2013). This phenomenon is known as “Inflamm-aging”. In older subjects, high levels of interleukin (IL)-6 , IL-1 tumor necrosis factor – α, and C-reactive protein are associated with an increased risk of morbidity and mortality. In particular, cohort studies have indicated that TNF-α and IL-6 levels are markers of frailty. The low-grade inflammation characterizing the aging process notably concurs at the pathophysiological mechanisms underlying sarcopenia. In addition, proinflammatory cytokines (through a variety of mechanisms, such as platelet activation and endothelial activation) may play a major role in the risk of cardiovascular events. Dysregulation of the inflammatory pathway may also affect the central nervous system and be involved in the pathophysiological mechanisms of neurodegenerative disorders (e.g., Alzheimer’s disease).

Drug Development for the elDerly The development of longevity drugs has evolved from a faroff goal into an industry priority. Several companies are working on developing drugs that target aging, and some of these drugs are currently in clinical trials.

In the longevity industry, there are nine hallmarks of aging which are thought to be the root causes of aging.

genomic instAbility Genomic instability refers to psychological stress, sun radiation, toxic chemicals, and biological agents which either di-

Not all frail elderly people will experience all the symptoms mentioned. This seems to be closely associated with remaining reserve capacity, and hence, with resilience.

rectly trigger replication errors in DNA, or induce DNA damage through reactive oxygen species activity. Our genomes are faced with possible damage on a daily basis. Genomes owe their integrity and stability to the inbuilt repair systems that fix this accumulated damage.

telomere Attrition The telomere theory of aging proposes that telomeres act as a protective cap for chromosomes and that as their length decreases with each division cycle, they lose their protective function. Telomere theory is one of the predominant hypotheses used to describe aging. Pharmacological attempts to restore telomeres are underway.

epigenetic AlterAtion The aging process can cause alterations to our epigenome, which can in turn lead to alterations in gene expression that can potentially change and ultimately compromise cell function. As an example, epigenetic alterations of the immune system can harm activation and suppress immune cells, leaving humans vulnerable to immune system failure and inflammation. Few pharmacological solutions currently exist.

loss of proteostAsis Loss of proteostasis is a common aging-related process and indicator of disease. This process is characterized by an accumulation of harmful or misfolded proteins and unwelcome aggregates. With age, the degradation of these proteins is impaired. We know that aging cells have reduced autophagy capability, and that lysosomes become less efficient at eliminating cellular waste. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and prion diseases are examples of pathologies linked to loss of proteostasis.

DeregulAteD nutrient sensing Metabolic activity is known to stress our cells. Caloric restriction is a preventive therapy for slowing metabolic dysfunction. Some byproducts of metabolism, such as mitochondrial dysfunction and oxidative stress, are harmful, and can dysregulate nutrient-sensing and lead to diabetes. There are several key metabolic signaling pathways that can regulate the speed of aging: IGF-1 and the IIS pathway, and the mTOR-Akt signaling axis. AMP-activated kinase and Sirtuins proteins also take part in nutrient sensing. All of these proteins are potential targets for anti-aging investigation. Intermittent caloric restriction remains the most widely recognized preventive therapy to slow down potential metabolic dysfunctions.

mitochonDriAl Dysfunction There are few drugs currently in development for mitochondrial dysfunction, but some are emerging in the area of regenerative medicine. Mitochondria are involved in the

metabolism of urea, cholesterol, and neurotransmitters, and are responsible for detoxification and free radical production, as well as for the digestion of fat, carbohydrates and proteins. Their dysfunctions lead to a number of systemic disorders, and many common aging pathologies have been found to have their roots in mitochondrial dysfunction. Mitochondrial dysfunction has been implicated in type 2 diabetes, atherosclerotic heart disease, cancer, Alzheimer’s disease, Parkinson’s disease and stroke. Mitochondrial dysfunction is thought to be one of the key reasons why humans age.

cellulAr senescence With age, a buildup of cells that refuse to die in order to be replaced takes place. These cells have impaired cellular function, reduce tissue repair, accumulate potentially cancer-causing mutations, and increase chronic inflammation. This phenomenon of the irreversible arrest of cell division cycles is called cellular senescence. Senescence is a universal process that affects almost all cells. With age, immune reactivity declines and some senescent cells escape immune clearance. By the time humans reach old age, they have a massive accumulation of senescent cells. The long-term presence of senescence cells within tissues can potentially promote age-related diseases and may even cause aging itself.

Science is charting a path towards achieving our goal of eternal life �or at least of living a longer life, free from disease� and there are already a number of potential options that can offer longevity and happiness.

stem cell exhAustion Stem cells can differentiate into many other cell types and serve as regenerative and renewing components within tissues. Stem cells replenish tissues with functional differentiated cells to maintain normal cellular and tissue functions. Since the number of stem cells declines throughout life, younger people have higher replenishing potential. Stem cells accumulate genetic mutations and damage with age, and thus tend to lose their differentiation capacity. Stem cell exhaustion is a hallmark of aging, as it represents a failure to renew tissues.

AltereD intercellulAr communicAtion As humans age, the electrical and chemical signaling systems between cells become corrupted, resulting in distorted signals. Corrupted messages lead to an imbalance in cellular communication. As cells age, they produce more inflammation signals, due to dysfunction in the immune systems and accumulation of tissue damage. The result is chronic inflammation and disease, including atherosclerosis, type 2 diabetes, obesity, and chronic peptic ulcer.

conclusions: Humans are always seeking options for a longer and fuller life. Aging is a natural phenomenon that interferes with the normal desire to avoid old age.

Science is charting a path towards achieving our goal of eternal life —or at least of living a longer life, free from disease— and there are already a number of potential options that can offer longevity and happiness.

References:

Fulop T, et al. (2010). Aging, frailty and age-related diseases. Biogerontology 11:547-563.

Yates FE. (2002). Complexity of human being: changes with age. Neurobiol Aging 23(1):17-19

Lipsitz LA. (2004). Physiological complexity, aging, and the path to frailty. Sci Aging Knowledge Envorin 2004 (16):pe16.

Bortz WM II (2002). A conceptual framework of frailty: a review. J Gerontol A Biol Sci Med Sci 57(5):M283-M288.

Pel-Little, et al (2009). Frailty: defining and measuring of a concept. J Nutr Health Aging 13(4):390-394.

De Lepeleire, et al (2009). Frailty: an emerging concept for general practice. Bt J Gen Pract 59(562):e177-e182.

Michaud M. et al. (2013). Proinflammatory Cytokines, Aging and Age-related diseases. JAMDA 14, 877 – 882.

Collangelo M. Current State of Longevity. 2019. Linkedin. https://bit.ly/379QUs1