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Health Protocols

Immune Senescence

How Aging Accelerates Immune Decline

Aging individuals’ immune systems respond less efficiently to challenges compared with those of younger people. For example, consequences of the flu are more severe in the elderly, with a lower likelihood of complete recovery and a higher risk of transition into chronic illness (Montecino-Rodriguez 2013; Mitchell 2010). An estimated 90% of influenza-associated deaths in the United States occur among persons aged 65 years or older, and most are related to cardiovascular and pulmonary complications (McElhaney 2012; Thompson 2003). Poor antibody response to vaccinations in the elderly adds to their vulnerability. Diminished immune system function is also evidenced by increased rates of autoimmune diseases and cancer in the elderly, and by increased susceptibility to infections. This well-recognized deterioration of immune function, or immune senescence, is a hallmark of aging (Pera 2015; Castelo-Branco 2014; Yu 2014; McElhaney 2012; Cannizzo 2011; Mitchell 2010; Thompson 2003; Lopez-Otin 2013).

Immune senescence also contributes to the enhanced vulnerability of older adults to cardiovascular disease, Alzheimer disease, metabolic syndrome, type 2 diabetes, and osteoporosis. These age-related afflictions share a common denominator: chronic, low-grade, systemic inflammation—a prevalent feature of aging that contributes to tissue damage and degeneration. Immune senescence is associated with a chronic pro-inflammatory state, which further accelerates immune system decline (Maijo 2014; Franceschi 2014; Lang 2013; Pera 2015; Lopez-Otin 2013).

Decline in Naïve T Cells

Naïve T cells originate from precursor cells in the bone marrow and mature in the thymus. These inexperienced T cells have yet to be activated by antigen exposure. Because of their immune inexperience, naïve T cells can be activated to recognize and respond to new challenges. Importantly, a vast supply of naïve T cells is needed to initiate a T-cell immune response to newly encountered antigens, such as new variations of the influenza virus, new antigens used in vaccinations, and cancer cells (Muller 2013; Naylor 2005; Maijo 2014).

After roughly age 70, there is a general decrease in naïve T cells. Furthermore, when compared with naïve T cells from younger people, naïve T cells from older individuals exhibit many functional defects, including impaired ability to multiply and become mature “effector” cells. As a result, the ability of the elderly to mount a successful immune response to new antigens is diminished. This impairs defense aginst microbes, reduces vaccine efficacy, and increases cancer risk (Weiskopf 2009; Hakim 2007; Maijo 2014).

Increasing Numbers of Senescent Memory T cells

Memory T cells are specialized T cells generated after an initial encounter with an antigen that persist long after the exposure has ended. Upon re-exposure to the antigen, memory T cells recognize the antigen and launch a rapid and vigorous response. Over time, exposure to multiple antigens increases the body’s pool of protective memory T cells (Montecino-Rodriguez 2013; Abbas 2009). However, memory T cells from older persons are often senescent, meaning they lost their ability to proliferate and have become dysfunctional (Maijo 2014; Chou 2013; Dock 2011).

Although unable to divide, senescent cells remain active, secreting high levels of pro-inflammatory molecules such as tumor necrosis factor-alpha and interleukin-6 (Chou 2013; Maijo 2014; Dock 2011; Baker 2011; Hazeldine 2013). Chronic inflammation triggered by senescent T cells may be a contributing factor in cardiovascular disease and other chronic diseases of aging (Yu 2014; Chou 2013). There is also evidence that senescent memory T cells may suppress other types of immune cells (Chou 2013; Dock 2011).

Senescence of memory T cells may result in part from lifetime exposure to common viral infections such as cytomegalovirus and Epstein-Barr virus. These viruses remain inactive in the body for decades, triggering a chronic, low-intensity response from memory cells and other adaptive immune cells. In addition to inducing chronic inflammation, this long-term, low-level T-cell activation can eventually contribute to T-cell dysfunction and senescence (Chou 2013; Dock 2011).

Decrease in Functional Natural Killer Cell Activity

High natural killer (NK) cell activity is associated with longevity and healthy aging, while reduced NK cell function is linked to increased illness and death from infections, atherosclerosis, and diminished antibody response to the flu vaccine (Weiskopf 2009).

NK cell function decreases with age (Hazeldine 2013; Beli 2014; Weiskopf 2009). Activated NK cells secrete immune-regulating cytokines, but activated NK cells from elderly individuals generate fewer cytokines than NK cells from younger people. The decline in NK cell function that accompanies human aging is associated with increased incidence of bacterial and fungal infections among the elderly (Hazeldine 2013; Weiskopf 2009).

Thymus Gland Atrophy

One of the most dramatic changes that occur in the aging immune system is atrophy (shrinking) of the thymus gland. Thymus atrophy is believed to contribute significantly to immune senescence (Palmer 2013; Griffith 2015), and thymus function decreases with age (Griffith 2015; Weiskopf 2009).

As the thymus atrophies, its production of naïve T cells declines (Griffith 2015; Weiskopf 2009). Along with accumulation of memory T cells, this contributes to a shift in T-cell population toward memory T-cell dominance. As a result, the ability to respond to new immunological challenges, including vaccines, is compromised, and susceptibility to infection, autoimmune disease, and cancer increases (Griffith 2015; Palmer 2013; Chou 2013).

Cimetidine and the Immune System

The over-the-counter heartburn medication cimetidine (Tagamet) may help combat immune senescence. This drug reduces histamine’s ability to stimulate stomach acid production by blocking special histamine receptors in the stomach, known as H2 receptors. It is primarily used to treat indigestion, heartburn, and peptic ulcers (NIH 2010; Pantziarka 2014). Although researchers have been investigating its other effects for decades, few people realize that cimetidine possesses immune-modulating and anti-cancer properties (Lefranc 2006; Pantziarka 2014; Li 2013).

Clinical trials have been conducted in which cimetidine has demonstrated therapeutic benefits as an adjunctive therapy for several types of cancer, particularly colon cancer, stomach cancer, kidney cancer, and melanoma (Pantziarka 2014).

Cimetidine’s benefits are thought to derive in part from its ability to modulate the influence of histamine on immune function and cancer metabolism. For example, histamine can shift the balance of cytokines and increase regulatory T-cell activity, leading to inhibition of other immune cells (Pantziarka 2014). Cimetidine may counter these effects. Studies in cancer patients found that cimetidine prevents treatment-related reductions in numbers of T cells, B cells, and NK cells, as well as overall anti-tumor immune activity (Li 2013; Bai 1999; Nishiguchi 2003; Adams 1994; Kikuchi 1986). Cimetidine has further been found to increase NK cell activity and enhance the cell-killing capacity of antibody-dependent immunity (Hast 1989; Zhang 2011; Wang 2008). Cimetidine has also been found in animals and laboratory research to enhance immune response to vaccines against the hepatitis B virus (Niu 2013; Wang 2008; Zhang 2011).

People with other health problems may also benefit from cimetidine’s immune-stimulating effects. In two randomized trials, cimetidine prevented immune suppression following heart surgery (Katoh 1998; Tayama 2001). Also, early research suggests cimetidine may reverse immune suppression related to burn injury (Kokhaei 2014) and herpes zoster (the virus that causes shingles), with cimetidine treatment leading to faster recovery (Komlos 1994; Miller 1989). Cimetidine has been found to increase immune responsiveness in mouse models of immune suppression (Gifford 1988; Jin 1986), and augment the stimulatory effect of interferon (a cytokine that activates immunity) on human NK cells (Hirai 1985).

Despite their similarities, other H2 blocking drugs such as ranitidine (Zantac) and famotidine (Pepcid) have not demonstrated the same immune-modulating effects as cimetidine (Hahm 1995; Kubota 2002; Hahm 1994), suggesting cimetidine may have unique properties that have not yet been fully characterized.

These findings suggest intermittent cimetidine cycles should be considered in an anti-immune-senescence regimen. Life Extension suggests aging individuals interested in maximizing their defense against immune senescence take 800 mg cimetidine daily for 60 days, once or twice yearly. Cimetidine should only be used intermittently to minimize possible risks associated with immune overactivity and increased risk of pneumonia (Arndt 2010; Nagler 1987; Eom 2011). As always, a healthcare provider should be consulted before embarking on any new medication regimen, over-the-counter or otherwise.

Overproduction of Interleukin-6

Immune senescence is associated with high levels of the inflammatory cytokine interleukin-6 (IL-6), while low IL-6 levels are common in healthy centenarians (Franceschi 2005).

In the elderly, elevated IL-6 is associated with twice the risk of death, as well as increased risks of dementia and Alzheimer disease, cancer, and frailty (Varadhan 2014; Garbers 2013; Gomez 2010; Ershler 2000; Harris 1999; Duarte 2016).

Cytomegalovirus

Infection with cytomegalovirus (CMV), a member of the human herpesvirus family, is very common. Most people do not have symptoms of CMV infection, and are not even aware they have it. As is the case with many herpesviruses, CMV remains in the body throughout life but is inactive (latent) most of the time. CMV can be reactivated and cause serious illness in people with a compromised immune system, such as those with cancer or AIDS (Schlick 2015; Michaelis 2009; CDC 2016a; Staras 2006).

CMV may be of particular concern for older individuals. Up to 90% of those over age 75 have persistent CMV infections (Staras 2006). An increasing number of studies suggest persistent CMV infection is associated with immune senescence, cardiovascular disease, frailty, and mortality (Sansoni 2014; Chou 2013; Savva 2013; Muller 2013; Pawelec 2009; Weiskopf 2009; Smithey 2012). CMV’s relevance in the context of immune senescence appears dependent upon the amount of immune attention required to keep this virus in check, which may vary from person to person. In some individuals, long-term CMV infection may trigger an expansion of memory T cells devoted to CMV and a contraction of naïve T-cell populations. This reduction of naïve T cells may impair the ability of the immune system to respond to new antigens associated with potentially harmful microbes, as well as new antigens in vaccines (Karrer 2009; Mekker 2012; Wang 2010; Vescovini 2014; Snyder 2011).