Immunity & Longevity 

Strategic Immunotherapy in the Treatment and Prevention of

Aging-related Diseases & Disorders—Coronary Heart Disease, Metabolic Syndrome & Non-Insulin-Dependent Diabetes Mellitus, Cancer

Dr. Karriem H. Ali, MD  

Abstract

Fundamentally, humankind has long thought of aging as a gradual, time-dependent decline in one’s well-being and quality of life, with an increased incidence and severity of debilitating chronic diseases.  However, the present basic and medical science argue for a fresh, more enlightened perspective. 

There is a vast body of scientific literature which indicates that immune dysregulation—specifically in that branch referred to as the “innate immune system”—may be the determinative factor for the seemingly inevitable functional decline of advancing age.  This dysregulation is characterized by a persistent, systemic low-grade over-reactive state of immune processes, which produce, in whole or in part, the inflammatory changes intrinsic to most of the chronic diseases that we associated with aging (e.g., cardiovascular diseases, Alzheimer's disease, insulin-resistance and diabetes, osteoarthritis, cancer). 

Here, we present an evidence-based synthesis gleaned from our current and ongoing laboratory and clinical research findings along with the existent knowledge in the field, to suggest that:

1)     Aging is a multifactorial clinical syndrome primarily resulting from progressive “immunosenescence”;

2)     Aging is a non-linear, experience-dependent process, rather than a linear time-dependent process; and

3)     The use of Allotypic Immuno-Modulators (AIMs) to achieve a persistent reversal of immunosenescence may well be the simplest common denominator available to solve the healthful longevity equation.

Background

Immunosenescence

The condition of decline in immune function associated with increasing age is referred to as “immunosenescence” in the literature by many thought leaders [ 1 ].   Immunosenescence is an insidious process which leads to impaired responses to antigen exposure, an increase in the rates of infectious disease morbidity and mortality (e.g., herpes zoster and M. tuberculosis), and of autoimmune disorders [1-4 ].

The phenomenon of immunosenescence involves characteristic transformations in the immune system, mainly expressed as a decrease in cellular functions. Quite surprisingly, these changes are typically of early onset, progressing further as an adult advances in age.  Individual immune status can be further depressed by the adverse effects of a number of lifestyle and environmental factors, including: stress, poor gastrointestinal function, toxic chemical and radiation exposure (including chemotherapy and radiation therapy).

Immunosenescence also appears to be directly associated with the phenomenon of age-related telomere shortening, which is known to reduce cellular proliferative capacity in the immune system in general, and of Natural Killer (NK and NKT) cells in particular [ 5 ].

Natural Killer (NK and NKT) Cells

Natural killer cells are an important component of the innate immune system, providing early defense against the propagation of cancer and viral infections [6, 7].  Immunohistologically, NK cells are defined as cytotoxic immune cells expressing the CD16 F_c receptor site and the CD56 NK receptor, but lacking a CD3/T cell receptor complex (CD3-CD16+CD56+).  Functionally, they are also immune cells that do not require major histocompatibility complex (MHC) recognition.  

Human NK cells may be divided into two distinct subpopulations based on their respective CD56 cell surface receptor densities: CD56^dim and CD56^bright NK cells [8 ].  CD56^dim cells make up roughly 90% of all CD56 positive NK cells, and effect cytotoxicity via the release of perforins and granzymes. CD56^dim cells can also bind to target cells forming conjugates.  CD56^bright cells differ from CD56^dim cells in that they are involved in cytokine secretion (IL-10, IL-13, IFN-γ, TNF-β, and GM-CSF) with the purpose of innate immune response regulation [9 ]. During dormancy, CD56^bright NK cells tend to be less cytotoxic than their CD56^dim counterparts.

Immunosenescence affects Natural Killer (NK and NKT) cells and phagocytic cells, in several ways, leading to an intrinsic impairment and diminished cell counts.  Studies show a comparatively weakened response to Interleukin 2 (IL-2) in NK cells from adult donors of advanced age, as well as a shrunken NKT cell population displaying altered lymphokine production [10, 11].  Due to the essential immunoregulatory role of NK and NKT cells, their impairment and diminution has a profoundly negative effect on the aging adult immune response.  

Anti-cancer immunity functional activity studies performed on adult donors of advanced age have further shown a diminished NK cell cytotoxicity against K562 tumor cells [12 ].   Additionally, adults of advanced age with relative NK cell depression demonstrate a tripled 2-year mortality risk in comparison to subjects with adequate NK cell levels [13 ].   Centenarians are considered as an exemplary model of healthy adult aging, however, and studies of this select population reveal well-preserved NK cell cytotoxic function [14 ].

 

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