Immune Senescence

Last Section Update: 04/2021

Contributor(s): Maureen Williams, ND; Robert Iafelice, MS/RD/LDN

Table of Contents

1 Overview

Summary and Quick Facts for Immune Senescence

The immune system is your body’s natural defense against foreign and potentially harmful substances. Immune senescence refers to the deterioration of the body’s immune system as a result of aging.
By reading this protocol you will gain valuable insights into the impact of aging on the immune system. You will also discover how positive lifestyle changes and immune-enhancing nutrients may support a youthful immune system as you age.
Several cases have shown that natural ingredients such as cistanche, reishi and pu-erh tea extracts may help restore healthy immune function.

As we age, our immune system function deteriorates, leaving us increasingly susceptible to health threats such as cancer, autoimmunity, infections, and chronic inflammation. This process is called immune senescence.

Scientists are studying various methods for countering immune senescence, including young stem-cell mobilized plasma transfusions. Research suggests old blood may contain pro-aging factors whose concentrations are diluted by young-blood transfusions, potentially causing rejuvenating effects.

In addition, several natural interventions, including cistanche, reishi and zinc may slow or potentially reverse the course of immune senescence.

How Aging Accelerates Immune Decline

Decreased numbers of naïve T cells, or cells that can easily be activated to recognize and respond to diseases like the flu and cancer

Increased numbers of senescent memory T cells that have lost their ability to divide and function properly and instead release pro-inflammatory molecules

Decreased natural killer (NK) cell activity, which is linked to increased illness and death from infections, atherosclerosis, and diminished response to the flu vaccine

Cytomegalovirus infection may be associated with immune senescence, cardiovascular disease, frailty, and mortality

Novel and Emerging Interventions

One or more components of young blood might be able to reverse some aspects of immune aging in humans; another emerging theory is that there may be factors in old blood that trigger immune system aging. Scientists, including some whose work Life Extension is supporting, are studying the effects of transfusions of young plasma fractions into aging recipients.

In a laboratory study, treatment of aged immune cells with granulocyte-colony stimulating factor (G-CSF) resulted in improvement in their function and mobility, and an increase in their number.

The over-the-counter heartburn medication cimetidine possesses immune-modulating and anti-cancer properties. Intermittent cimetidine cycles should be considered in an anti-immune-senescence regimen.

Diet and Lifestyle Considerations

Caloric restriction in animals has been shown to prolong lifespan and delay aging, and to confer a more youthful T-cell profile.

In a 2014 review, greater adherence to a Mediterranean diet was associated with significantly reduced levels of important markers of inflammation.

Exercise and stress management may improve immune function.

Integrative Interventions

Cistanche: A formula with cistanche as the primary ingredient conferred multiple benefits in a clinical trial including increased helper T cells, improved relative proportions of types of T cells, and greater NK cell activity.

Reishi: A rigorous review of controlled clinical trials found cancer patients who used reishi along with chemotherapy and radiation showed increased percentages of several subsets of T cells and may have slightly increased NK cell activity.

Pu-erh tea extract: In a randomized controlled trial in individuals with metabolic syndrome, pu-erh tea extract significantly decreased levels of inflammatory markers, while increasing levels of an anti-inflammatory molecule.

Enzymatically modified rice bran: Enzymatically modified rice bran has been shown to enhance the number and function of immune cells, particularly NK cells.

Zinc: In a placebo-controlled study in healthy older volunteers, daily intake of zinc for one year resulted in a 67% reduction in incidence of infections and reduced levels of an inflammatory cytokine.

2 Introduction

As we age, we become increasingly susceptible to health threats such as cancer, autoimmunity, and infections (Pera 2015; Agarwal 2010; Franceschi 2014). One important cause of this vulnerability is immune senescence—the insidious deterioration of immune system function that occurs during aging (Goronzy 2013; Aw 2007; Franceschi 2014; Pera 2015).

Over time, our ability to fend off bacteria and viruses diminishes, our response to vaccinations weakens, and critical anti-cancer defenders called natural killer (NK) cells become increasingly impaired. At the same time, smoldering, persistent inflammation runs rampant in our aging bodies (Mekker 2012; Franceschi 2014; Pera 2015; Mitchell 2010). Our immune cell diversity declines as well during aging, reducing our defense against novel pathogens. These changes are all due in part to immune senescence (Zhang 2016; Candore 2008; Agarwal 2010; Muller 2013; Maijo 2014).

Scientists are studying various methods for countering the detrimental effects of aging on immune function. One approach that has garnered considerable interest is young stem-cell mobilized plasma transfusions. Early studies suggested that joining the circulatory systems of young and old mice reversed some age-related changes in older mice, leading to the assumption that young blood contained anti-aging factors responsible for these benefits. Newer research suggests old blood may contain pro-aging factors whose concentrations are diluted by young-blood transfusions (Rebo 2016; Conboy 2005; Villeda 2011; Villeda 2014). Currently, studies are underway to determine if young blood transfusions or elimination of pro-aging factors in old blood can bolster the function of aging human immune systems and promote longevity (Karmazin 2016; Sha 2016). More advanced studies using stem cell mobilized plasma proteins and immune factors are being planned.

One trailblazing physician-scientist in South Florida, Dipnarine Maharaj, MD, who specializes in stem cell transplantation and research, has explored the potential of using granulocyte-colony stimulating factor to activate immune stem cells and combat immune senescence (Maharaj 2014). Life Extension is engaged in funding cutting-edge research of this nature, as it provides crucial insights into the intricate biology that underlies age-related immune decline and may clarify methods aging individuals can use to circumvent the ravages of immune senescence.

Another intriguing intervention for bolstering immune function in advancing age is the common over-the-counter heartburn medicine cimetidine. This drug has overlooked immune-enhancing properties and may protect against a number of cancers. Also, results from animal studies indicate cimetidine enhances immune response to antiviral vaccines (Pantziarka 2014; Wang 2008) and may be used on a short-term basis to bolster immune defenses.

Few people are aware that a common virus can also contribute to immune senescence. Cytomegalovirus (CMV) lingers in a latent state in a significant portion of the population. This means that you could harbor this virus and not even know it. Latent CMV infection may shift the balance of immune cells toward memory T cells specialized for CMV and away from naïve immune cells that combat novel pathogens (Derhovanessian 2010). Also, CMV infection has been associated with numerous diseases, including deadly glioblastoma brain cancer. Fortunately, interventions exist that may help offset the immune compromise caused by latent CMV infection. Enzymatically modified rice bran, for example, may help reduce CMV burden and mitigate the consequences of latent infection (Ghosh 2010; Ray 2013).

In addition, a variety of natural interventions may slow or potentially reverse the course of immune senescence. Evidence from clinical and preclinical studies indicates that natural products such as reishi mushroom, cistanche, and pu-erh tea possess potent immune-modulating properties that can be harnessed to deter immune senescence (Yonei 2011; Batra 2013; Wachtel-Galor 2011; Kladar 2015; Chu 2011).

Lifestyle improvements including regular exercise, stress management, adequate sleep, and an anti-inflammatory eating pattern (such as the Mediterranean diet) can also suppress chronic inflammation and support the immune system (Simpson 2015; Ganz 2012; Witek-Janusek 2008; Carlson 2007; Oliviero 2015; Mena 2009). Though requiring more dedication, caloric restriction has been shown to improve immune cell function and promote longevity (Ahmed 2009; Ravussin 2015).

This protocol will explain important aspects of the immune system and the roles of key immune cells. In particular, you will gain valuable insights into how aging accelerates immune senescence, and how positive lifestyle changes can counter these effects. This protocol will also reveal exciting new information about a variety of immune-enhancing natural products and nutrients that may help you maintain youthful immune system function into advancing age.

3 Understanding The Immune System

The immune system includes two closely related components—innate immunity and adaptive immunity (Chaplin 2010; Parkin 2001).

Innate Immune System

Innate immunity is the body’s first response to foreign and potentially harmful substances. It is ready to mobilize rapidly, and can nonspecifically attack particles that trigger an immune response (antigens) (Drake 2010; Chaplin 2010; Abbas 2009). Important components of the innate immune system include:

Physical and chemical barriers, such as the skin and its secretions, the lining of the gastrointestinal and respiratory tracts, and stomach acid (Drake 2010; Abbas 2009; Storey 2008).
Phagocytic white blood cells, immune cells (eg, neutrophils, macrophages, monocytes, and dendritic cells) that engulf and destroy invaders and activate the adaptive immune system (Chaplin 2010; Drake 2010).
Natural killer cells or NK cells, specialized immune cells that act rapidly to destroy abnormal cells, especially tumor cells and virus-infected cells (Iannello 2013; Wang 2012; Chaplin 2010; Storey 2008; Abbas 2009).
Acute-phase proteins are involved in both innate and adaptive immunity. Some acute-phase proteins, including C-reactive protein and fibrinogen, are useful clinical markers of inflammation (Jain 2011; Storey 2008; Abbas 2009; Du Clos 2004; Heidari 2012).

Adaptive Immune System

If the innate defense system does not eliminate the threat, the next level of defense is the adaptive immune system (Drake 2010; Abbas 2009), which responds specifically to individual antigens. The adaptive immune system includes antibody-mediated immunity and cell-mediated immunity (Delves 2014).

Antibody-mediated immunity. In antibody-mediated immunity, immune cells known as B cells produce and secrete antibodies into the blood and other tissues. Antibodies recognize and bind to specific antigens that occur on the surface of bacteria, viruses, fungi, or allergens, (or in the case of autoimmune conditions, self-cells,) in order to eliminate them or tag them for destruction by other immune cells (Delves 2014; Drake 2010; Abbas 2009).
Cell-mediated immunity. Cell-mediated immunity relies on T cells, and can be active against infected cells, as well as phagocytic cells that have already engulfed harmful micro-organisms (Rezzani 2014; Abbas 2009; Griffith 2015; Mitchell 2010; Drake 2010). The thymus gland, located in the chest behind the breastbone, is responsible for the production of mature T cells. Age-related atrophy of the thymus plays a major role in immune senescence (Rezzani 2014; Abbas 2009; Griffith 2015; Mitchell 2010). Three important T-cell types that participate in cell-mediated immunity are helper T cells, cytotoxic T cells, and regulatory T cells:
- Helper T cells. Helper T cells augment the function of other immune cells. They promote antibody production by B cells, and help other immune cells recognize and kill microbes and infected cells (Abbas 2009).
- Cytotoxic T cells. Like NK cells, cytotoxic T cells directly attack and destroy foreign, infected, and abnormal cells, including cancerous and non-self cells (Waterhouse 2006; Delves 2014; Drake 2010; Storey 2008).
- Regulatory T cells. Regulatory T cells generally control or terminate an immune response to a perceived invader, minimizing tissue damage and helping protect against conditions in which the immune system reacts excessively, such as autoimmune diseases and allergies (Delves 2014; Drake 2010; Dimeloe 2010; Storey 2008; Belkaid 2007).

Emerging research suggests regulatory T cells may play a role in immune senescence. Some types of regulatory T cells appear to accumulate with age and may weaken the immune response to pathogens or malignant cells. At the same time, it appears that numbers of other types of regulatory T cells remain the same or even decline (Jagger 2014). Furthermore, the function of regulatory T cells may change with age (Jagger 2014; Fessler 2013; Schmitt 2013). Thus, a balanced and properly functioning array of regulatory T cells appears to be necessary to avoid smoldering chronic inflammation while maintaining immune competence and protection against infections and cancer.

Overall, the impact of regulatory T cells in the context of immune senescence cannot be stated categorically, and may vary among individuals. For example, a person with a history of autoimmune disease could potentially benefit from increased regulatory T-cell numbers or activity, while someone prone to infections or cancer but without a history of autoimmune disease might benefit from decreased regulatory T-cell activity (Belkaid 2007; Jagger 2014; Fessler 2013).

Microbiota and Immunity

The approximately 30 trillion bacteria that inhabit our bodies are collectively referred to as the microbiota. Most of these bacteria colonize the gastrointestinal tract, where nearly 70% of the immune system resides (Maranduba 2015; Vickery 2011; Vighi 2008; Sender 2016).

Disruption in the balance of the intestinal microbiota can increase inflammation, lead to infection, and contribute to disease development (Duncan 2013). Antibiotics and other drugs, toxins, diet, and harmful microbes can disrupt the proper balance of the gut microbiota (Carding 2015; Modi 2014). Changes in the populations of gut microbes may also be associated with aging (Duncan 2013).

Compared with the diet of people living in less-developed countries, the typical Western diet tends to be lower in fiber and higher in fat and refined carbohydrates. These dietary differences influence the composition and function of gut microbes, which can in turn modify immune function (Graf 2015; Noverr 2004; Vieira 2014).

The immune-enhancing and life-prolonging effects of caloric restriction may be partially explained by alterations in the gut microbiota (Vieira 2014). Animal and clinical studies have shown that caloric restriction may increase beneficial microorganisms in the gut and decrease detrimental ones. Caloric restriction may also reduce the amount of immunity-provoking compounds (ie, antigens) taken up by the gut, reducing the stress on the immune system (Festi 2014; Simoes 2014; Oh 2016; Zhang 2013).

Clinical trials have shown probiotics can enhance immune function in the elderly, potentially reducing the frequency and severity of infectious diseases (Maijo 2014; Duncan 2013; Ibrahim 2010; Candore 2008). Probiotics are live microorganisms that, when ingested via food or supplements, benefit health by restoring or maintaining a favorable balance of the intestinal microbiota (Homayouni Rad 2013; Duncan 2013; Homayoni Rad 2016).

One randomized controlled trial that enrolled over 700 healthy volunteers showed a preparation containing probiotics (Lactobacillus plantarum, Lactobacillus rhamnosus, and Bifidobacterium lactis), lactoferrin, and prebiotics (non-digestible fibers that can serve as a food source for benefical gut bacteria) reduced the incidence of respiratory diseases during the cold season. The probiotic formulation reduced the number, severity, and duration of upper respiratory infections; improvements in bowel function were also observed (Pregliasco 2008). In another trial, the same probiotic blend, given with colostrum (antibody-rich “first milk,” produced in late pregnancy), reduced flu incidence compared with vaccination and with no treatment (Belcaro 2010). Another probiotic, Bacillus subtilis CU1, enhanced the immune response and reduced the frequency of respiratory infections in elderly study participants (Lefevre 2015).

4 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).

Chronic Viral Infection and Immune Senescence

Viruses that affect humans are generally known for the acute infections they cause, but many viruses have a quieter long-term presence in the body, comprising the vast human virome. As with other parts of the microbiome, humans have co-evolved with viruses for millions of years and have a mutually dependent relationship with them (Nikolich-Zugich 2017; Koonin 2021). Importantly, these latent viruses can become pathogenic as conditions in the body change (Koonin 2021).

The majority of the human virome is made up of bacteriophages—viruses that infect bacteria. However, some viruses that infect human cells persist as latent infections and are important members of the human virome.

Examples include (Nikolich-Zugich 2017; Koonin 2021):

herpesviruses (eg, herpes simplex virus, varicella (shingles) virus, Epstein-Barr virus, and cytomegalovirus [CMV]);
flaviviruses (eg, hepatitis C viruses); and
retroviruses (eg, human immunodeficiency virus [HIV])

It is estimated that every adult carries between five and 10 persistent viruses, most of which cause no evident problems in healthy individuals (Nikolich-Zugich 2017). In fact, long-term carriage of these viruses, especially herpesviruses, may contribute to immune regulation by producing molecules that inhibit inflammation and by maintaining active T-cell populations and enhancing production of interferon, an important mediator of the antiviral response. However, a decline in health status due to aging, disease, immunosuppressive therapies, stress, or lifestyle factors can disturb the balance between latent viruses and the immune system, potentially leading to viral reactivation and acute illness (Sehrawat 2018; Moss 2019; Koonin 2021). In addition, prolonged activation of T cells by latent infectious viruses appears to induce gradual exhaustion of these cells, and contribute to progressive immune dysfunction (Nikolich-Zugich 2017; Franco 2020). Chronic CMV infection has drawn particular attention for its possible role as a contributor to immune senescence.

Most humans are exposed to CMV early in life, such that 50–90% of elderly adults are chronic carriers (Nikolich-Žugich 2020). The immune response to CMV results in progressive expansion of memory T cells relative to naïve T cells, a pattern characteristic of senescence (Tu 2016; Nikolich-Žugich 2020). In addition, T cells targeting CMV have been found to produce more inflammatory cytokines and have less capacity to proliferate when activated (Humphreys 2020). Furthermore, conditions related to aging and immune senescence, including cardiovascular disease, Alzheimer disease, and frailty, have been correlated with persistent CMV infection in elderly adults (Nikolich-Zugich 2017).

Other chronic viral infections may also induce immune dysregulation. T cells from individuals with chronic hepatitis C virus infection show signs of senescence, as well as DNA damage that may interfere with their appropriate activation (Humphreys 2020). Chronic HIV infection has been noted to cause T-cell abnormalities similar to those seen with aging, including abnormal numbers and activity of regulatory T cells, lower naïve-to-memory T-cell ratio, and suppressed vaccine responsiveness (Humphreys 2020; Yang 2020; Rothan 2021).

Recent research suggests antiviral therapies may help repair the damaging effects of chronic viral infections on the immune system. Signs of HIV- and hepatitis C-related immune senescence appear to be partially mitigated by treatment with conventional antiretroviral medications (Casey 2019; Humphreys 2020). So far, effective treatments against chronic latent herpesvirus infections have not yet been discovered.

The effect of interactions between novel infectious viruses and the existing virome is a topic of emerging research. One possibility being explored is that illnesses caused by new viruses, such as SARS-CoV-2, may be more severe due to chronic viral infection-induced immune senescence or reactivation of latent herpes simplex virus or CMV (Le Balc'h 2020; Moss 2020; Söderberg-Nauclér 2021).

5 Assessing Immune Function

A variety of laboratory tests can be used to assess immune function (Serrano-Villar 2014; NIH 2012; LabCorp 2015; MayoClinic 2015a; Quest 2015; O'Sullivan 2013; MayoClinic 2015b; Coventry 2009; Shrivastava 2015; CDC 2016b; Licastro 2016). Some common tests are listed in Table 1. There are numerous other tests available that assess various aspects of immune system function, and a physician who suspects a specific immune-related problem may order tests not included in this list. The results from tests listed in Table 1 will provide general insights into immune system function in the context of immune senescence. In order to best evaluate general immune system health, these tests should be performed while the patient is well and not suffering from acute illness or recovering from trauma, as these conditions can impact the results.

Table 1: Laboratory Assessment of Immune Parameters
Test	Description
White blood cell (WBC) count	Abnormal levels may be sign of infection, blood cancer, or immune system disorder
Cytomegalovirus (CMV) IgM and IgG	Aids in diagnosis of CMV infection or reactivation; positive CMV IgM indicates recent CMV infection or reactivation; positive CMV IgG indicates exposure to CMV, but a single test does not distinguish between past or recent infection
Epstein-Barr Virus (EBV) Antibodies	Assesses persistent EBV infection, which may contribute to immune senescence
Human Herpesvirus 6 (HHV-6) IgG, IgM	Assesses total antibodies for HHV-6
Natural Killer (NK) cell Function	Assesses functional (ie, cell-killing) capacity of NK cells
Natural killer (NK) cell surface antigen (CD3-CD56+ Marker Analysis)	Determines levels of NK cells in circulation
Complement C3 and C4	Low levels of C3 and C4 may be associated with autoimmune diseases such as systemic lupus erythematosus
C-reactive protein (hs-CRP)	Highly sensitive marker of inflammation that indicates immune activation, possibly due to conditions such as cancer, infection, injury, or autoimmune disease; correlates with cardiovascular risk
Cortisol and dehydroepiandrosterone sulfate (DHEA-S)	Cortisol is immunosuppressive, while DHEA stimulates immune function; an imbalance between these hormones may contribute to immune dysregulation
Cytokines, eg, TNF-α and interleukins IL-1beta, IL-6, IL-8	Proteins that are critical mediators of the inflammatory response
Antinuclear antibodies (ANA)	Elevated in some autoimmune diseases
Immunoglobulins IgA, IgG, IgM	Elevated in some autoimmune diseases, multiple myeloma, and acute and chronic infections; decreased in immune deficiencies
T-Lymphocyte helper/suppressor profile	May be helpful in assessing immunodeficiency states

6 Novel And Emerging Interventions

Parabiosis and Immune Function

Research dating back to the late 1800s is the basis of burgeoning interest in the anti-aging effects of so-called young blood. The experimental procedure that initially proved that animals’ circulatory systems could grow together and become joined (Bert 1864), referred to as parabiosis, was later used to demonstrate that older mice can live longer when their circulation is joined to younger mice (Ludwig 1972).

In early animal research, pairing old and young mice through parabiosis was found to have a positive impact on the bone density of the old mice (Horrington 1960). More recent animal research suggests parabiosis can help restore youthful tissue-regenerating activity in older stem cells (Conboy 2005). In one compelling study, growth and development of neurons were found to increase in old mice, and decrease in young mice, when their circulatory systems were connected (Mendelsohn 2011). Another study found brain plasticity and cognitive function were notably enhanced in aged mice joined through parabiosis to young mice. The authors of this study commented, “exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level” (Villeda 2014).

The effects of young blood on older animals are believed to be mediated, at least in part, by immunologic mechanisms. Emerging evidence suggests age-related diminishment of regenerative capacity in tissues such as muscles and neurons may be related to changes in immune signaling (Schiaffino 2016; Villeda 2013). Parabiosis has also been demonstrated to transfer immune tolerance: animal experiments have demonstrated that parabiosis can dampen or eliminate toxic immune reactions to foreign chemicals and tissue transplants (Polak 1975; Andresen 1957). This ability to transfer immune tolerance from one organism to another may have implications for future research into treatments for conditions related to immune hyperactivity, such as autoimmune diseases and allergies.

Researchers are exploring the possibility that one or more components of young blood might be able to reverse some aspects of immune aging in humans; conversely, there may be factors in old blood that disrupt normal stem cell activity and trigger immune system aging (Pishel 2012; Mendelsohn 2011).

One factor in young blood identified as potentially responsible for some anti-aging effects is called growth differentiation factor 11, or GDF11. Some research suggests levels of GDF11 decline with age, and restoration of GDF11 levels may reverse some manifestations of aging (Loffredo 2013). However, this area of research remains controversial, as not all studies have confirmed the anti-aging effects of GDF11 (Hinken 2016).

Recently, an alternative theory explaining the benefits of young blood transfusions has emerged. This newer perspective suggests that rather than providing anti-aging factors to older transfusion recipients, young blood may dilute concentrations of pro-aging factors that accumulate with age in the blood of older individuals. And indeed, old blood transfused into young animals has been shown to exert detrimental pro-aging effects in several tissue types as well as diminish some measures of physical performance (Rebo 2016).

Life Extension and other forward-thinking research organizations are currently organizing clinical studies that will help clarify the potential therapeutic benefits of factors in young blood and/or removal of pro-aging factors in old blood. Those interested in more information about these initiatives can fill out the information request form on this webpage: https://health.lifeextension.com/landingpages/stem.aspx

As of late-2016, an ongoing trial is investigating the effects of transfusions of plasma from individuals aged 16 to 25 into those aged 35 or older. This trial will assess the effects of these young-blood transfusions on a battery of biomarkers of aging (Ambrosia LLC 2016). Data from this and other similar trials promise to help establish the theoretical and practical framework that may allow this novel therapy to help aging individuals avoid the perils of immune senescence.

Granulocyte-colony Stimulating Factor

Granulocyte-colony stimulating factor (G-CSF) is a protein growth factor made by the body that stimulates production of neutrophils in the bone marrow. A G-CSF drug, filgrastim (Neupogen), is used to bolster low neutrophil counts and decrease risk of infection, particularly in some patients undergoing chemotherapy. Filgrastim can also increase the migration of blood-forming stem cells from the bone marrow into circulation (Arvedson 2015; Brender 2006; Bendall 2014; Gold Standard 2016).

Age-related immune senescence leads to reduced neutrophil function, mobility, and antibacterial activity (Butcher 2000; McLaughlin 1986; Schröder 2003). In a laboratory study, treatment of aged neutrophils with G-CSF resulted in improvement in their function and mobility, and an increase in the number of viable neutrophils (Wolach 2007).

One pioneering physician in South Florida, Dipnarine Maharaj, MD, has explored utilizing G-CSF to activate lymphoid stem cells and combat immune senescence (Maharaj 2014).

Overall, there is evidence to suggest G-CSF may represent a novel tool in the battle against age-related immune senescence. Continued research in this area is needed to improve our understanding of how neutrophils and overall immune system function in older individuals will respond to G-CSF treatment.

Senolytic Activators

Senolytic activators represent an exciting class of emerging therapeutics in aging science. They selectively target senescent cells (ie, cells that have stopped dividing properly and can promote an inflammatory response) and remove them or decrease their negative impact. Senescent cells have been implicated in many age-related diseases. Senolytic agents may improve cardiovascular functioning, promote bone health, increase insulin sensitivity, support healthy metabolism, and rejuvenate stem cells (Soto-Gamez 2017).

Quercetin plus Dasatinib. Quercetin, a bioflavonoid found in foods such red wine, onions, apples, berries, and green tea, has potent anti-inflammatory and free radical-scavenging properties. It has been shown to induce cell death in senescent cells, decreasing their numbers in human fat tissue cultures (Zhu 2015). The combination of quercetin plus dasatinib, a chemotherapy drug that inhibits cell proliferation, was also found to decrease the secretion of proinflammatory cytokines associated with age-related frailty by senescent cells (Xu 2018). It has also been postulated that quercetin may silence expression of pro-survival gene networks in senescent cells, helping facilitate cell death of dysfunctional, senescent cells (Zhu 2015).

In animal research, intermittent oral administration of quercetin plus dasatinib—to naturally aged mice and young mice that received transplanted senescent cells—improved physical function and increased post-treatment survival by 36% (Xu 2018). In addition, a single course of quercetin plus dasatinib reduced senescent cell burden, improved heart and blood vessel function, and increased exercise capacity in mice. Periodic administration extended the lifespan of some mice, delaying age-related pathology and dysfunction long after treatment was discontinued (Zhu 2015).

Theaflavins. Theaflavins are some of the polyphenolic compounds that add red hues to black tea. Preclinical evidence indicates these compounds may have beneficial effects against cancer, atherosclerosis, obesity, osteoporosis, periodontal disease, inflammatory disorders, and bacterial and viral infections (Noberini 2012; Takemoto 2018). Theaflavins and other black tea polyphenols appear to inhibit tyrosine kinases, a group of enzymes involved in cell proliferation, and may also suppress certain tissue growth factors involved in senescence (Noberini 2012; Tominaga 2015).

In one study, a black tea extract containing theaflavins extended the lives of fruit flies by altering gene expression and reducing oxidative stress (Peng 2009). Another study showed theaflavins decreased radiation-induced senescence and oxidative stress in blood-cell-producing stem cells and prolonged survival in certain groups of irradiated mice (Han 2017).

7 Diet and Lifestyle Considerations

Caloric Restriction

The goal of caloric restriction is to reduce total caloric intake while maintaining optimal nutrition. This may be best accomplished by eating a diet primarily composed of low-calorie, nutrient-dense foods such as vegetables, fruits, legumes, nuts and seeds, and whole grains; limiting intake of animal products; and avoiding calorie-dense, nutrient-poor foods (Rizza 2014). Caloric restriction in animals has been shown to prolong lifespan and delay aging, and to confer a more youthful profile of T cells (Ahmed 2009; Fernandes 1997; Michan 2014).

In humans, long-term caloric restriction results in metabolic changes that reduce the risk of a number of age-related diseases including type 2 diabetes, cardiovascular disease, and cancer (Steven 2015; Rizza 2014; Bales 2013; Lefevre 2009; Meyer 2006; Fontana 2004; Stein 2012). In a clinical study, six months of caloric restriction significantly improved the ability of T cells to reproduce in response to foreign antigens (Ahmed 2009).

Studies in animal models have demonstrated that caloric restriction can improve multiple aspects of immune activity, particularly T-cell function (Jolly 2004; Messaoudi 2006; Nikolich-Zugich 2005). In a study in mice, caloric restriction was shown to maintain youthful function of the thymus gland and reduce immune senescence during aging. Compared with mice fed freely, calorie-restricted mice had greater proliferation and diversity of T cells (Yang 2009).

Further reading about the benefits of reducing caloric intake is available in Life Extension’s Caloric Restriction protocol.

Mediterranean Diet

The Mediterranean diet is a dietary pattern based on foods and drinks traditionally consumed by people in the region surrounding the Mediterranean Sea (Oldways 2016). The Mediterranean diet has been shown to protect against several age- and inflammation-related conditions including diabetes, atherosclerosis, obesity, cancers, and neurodegenerative diseases. The Mediterranean diet is primarily characterized by inclusion of olive oil, fruits, vegetables, legumes, whole grains, nuts, and seeds; with moderate amounts of fish, poultry, cheese, yogurt, and eggs; limited inclusion of red meat, cured meat products, and foods rich in refined sugars; and low-to-moderate alcohol intake, usually in the form of red wine consumed with meals (Casas 2014; Estruch 2010).

In a 2014 review of 17 clinical trials, greater adherence to a Mediterranean dietary pattern was associated with significantly reduced levels of interleukin (IL)-6 and high-sensitivity C-reactive protein, two important markers of inflammation (Schwingshackl 2014; Coventry 2009; Ershler 2000; US Department of Health and Human Services 2015).

Exercise

Regular moderate-intensity exercise can strengthen resistance to infection and improve immune system function. Single bouts of moderate-intensity exercise have even been used to improve response to vaccines. On the other hand, prolonged, excessive high-intensity exercise (ie, over-training) temporarily suppresses immune function and increases vulnerability to infection (Simpson 2015; Gleeson 2013; Zheng 2015).

Several human studies have indicated that moderate exercise may combat immune senescence (de Araujo 2013; Simpson 2011; Simpson 2010; Spielmann 2011; Woods 2009). In a study in sedentary older adults, participants randomized to 10 months of moderate cardiovascular exercise exhibited improvements in antibody responses to influenza vaccine compared with elderly individuals who only engaged in flexibility and balance exercises (Woods 2009).

In a study in elderly women, two years of regular physical activity increased production of IL-2—an important regulator of immune response that ordinarily decreases with age (Drela 2004). A 2011 study demonstrated that aerobic fitness is associated with reduced accumulation of senescent T cells (Spielmann 2011).

The effects of high levels of physical activity were evaluated in an observational cohort study of 125 adults aged 55 to 79 years who are master cyclists. Compared with 75 age-matched older adults who do not routinely exercise, the cyclists were shown to have more markers of a robust immune system. Older, physically active adults had significantly lower levels of immune senescence markers, including lower Th17 cell polarization and higher proportions of regulatory B cells. Lower levels of Th17 cells, which are T cells that have been shown to suppress the immune system, together with higher levels of regulatory B cells, may help decrease the risk of age-associated inflammatory autoimmune disease. Older adult cyclists also had cytokine signatures that promote thymus health—the key organ in which T cells mature. Furthermore, T-cell levels in the cyclists were comparable with those of much younger adults (aged 20 to 39 years). In contrast, inactive older adults had lower levels of T cells compared with both older adult cyclists and younger adults. Taken together, these results suggest that maintaining physical activity may delay immune senescence (Duggal 2018).

Stress Management

Chronic stress causes dysregulation of innate and adaptive immune responses by promoting persistent systemic inflammation and suppressing immune cells (Morey 2015; Dhabhar 2014). When sustained stress diminishes immune function, it can allow latent viruses such as cytomegalovirus to escape immune system control. Frequent reactivation of latent viruses can then further strain the immune system (Morey 2015). Chronic stress, and the accompanying chronic elevation of the stress-induced adrenal hormone, cortisol, appear to contribute to immune senescence (Bosch 2009; Bauer 2015). In fact, the ratio of cortisol to another adrenal hormone, dehydroepiandrosterone (DHEA), may be an important determinant of immune senescence (Bauer 2008).

In studies on patients with early-stage breast cancer, stress management interventions have been shown to improve cellular immune function and reverse pro-inflammatory gene expression in circulating immune cells (Antoni 2012; McGregor 2004). Stress management training in patients with rheumatoid arthritis resulted in decreased levels of stress-induced IL-8—an inflammatory cytokine (de Brouwer 2013). See Life Extension’s Stress Management protocol for more detailed information.

Sleep

Lack of sleep can weaken immune function and increase susceptibility to respiratory infections, including the common cold, and chronic lack of sleep may be associated with an increased risk of death (Prather 2015; Ibarra-Coronado 2015; Wilder-Smith 2013; Aldabal 2011). Sleep deprivation is associated with elevated cortisol levels, as well as higher daytime levels of inflammatory cytokines including IL-1, IL-6, and tumor necrosis factor-alpha (Aldabal 2011; Hirotsu 2015). A study in individuals aged 61‒86 found even a single night of partial sleep deprivation induced patterns of gene activation associated with biological aging (Carroll 2016).

The adverse effects of poor sleep include functional changes in regulatory T cells and other cells of the adaptive immune system, as well as reduced numbers of NK cells and T and B cells (Zuppa 2015; Bollinger 2009).

Reduced sleep has been shown to alter the balance between antibody-mediated and cell-mediated immunity (Ganz 2012). In one study, participants allowed regular sleep the night after vaccines had markedly superior long-term antibody responses compared with those who stayed awake that night. Another study showed sleep-deprived individuals had a significantly lower antibody response 10 days after immunization than those who had normal sleep (Lange 2003; Spiegel 2002). See Life Extension’s Insomnia protocol for more detailed information.

8 Nutrients

Cistanche

The Cistanche deserticola (C. deserticola) plant has been used historically in traditional medicinal systems as a remedy for chronic infections and other illnesses. C. deserticola contains an array of bioactive compounds (Zhang 2014; Li 2008; Jiang 2009), some of which have been shown to have antiviral, antibacterial, anti-tumor, and immunomodulatory properties (Fu 2008; Zhai 2007).

In animal models of accelerated aging and immune decline, C. deserticola extract extended lifespan and reversed multiple laboratory indicators of immune senescence. Cistanche supplementation led to significant increases in naïve T cells and NK cells, reductions in memory T cells, and decreased levels of the inflammatory cytokine interleukin-6 (IL-6) (Zhang 2014; Abe 1994; Butterfield 2005).

Cistanche extract’s ability to improve immune function was examined in a 12-week trial in 25 aging individuals. Cistanche was the principal ingredient in the test product, which also included vitamin E, vitamin B₆, coenzyme Q₁₀, zinc, and fucoidan. The product conferred multiple benefits including increased helper T cells, improved relative proportions of types of T cells, and greater NK cell activity. There were also considerable improvements in tests of vascular function, and study volunteers reported decreased fatigue (Yonei 2011).

Reishi

Reishi (Ganoderma lucidum) is a medicinal mushroom that has been used in Asia for over 2000 years for immune system support. Reishi contains polysaccharides, triterpenoids, and other potentially therapeutic compounds. Laboratory and animal studies have shown reishi polysaccharides have immunomodulatory, anti-tumor, and cell-killing effects that appear to derive in part from their ability to influence T cells, NK cells, and macrophages (Batra 2013; Jin 2012; Xu 2011).

The beta-glucan portion of reishi polysaccharides has been found to stimulate both innate and adaptive immune responses (Jin 2012). Other reishi compounds have demonstrated antiviral properties, including activity against herpes simplex virus, hepatitis B virus, and Epstein-Barr virus. Reishi constituents have also been shown to inhibit the growth of yeast and E. coli bacteria (Avtonomova 2014; Li 2005; Ma 2011; Iwatsuki 2003; Li 2006; Vazirian 2014).

These immune-enhancing effects may help explain the results of an animal study in which reishi-supplemented mice outlived control mice by a significant margin (Wu 2011). In another study, a product containing green tea extract and a reishi extract high in polysaccharides and triterpenes stimulated the proliferation of immune cells, including B cells, T cells, and NK cells, and inhibited malignancy in mice (Chen, Zhang 2007).

A rigorous review of controlled clinical trials found cancer patients who used reishi along with chemotherapy and radiation were 50% more likely to respond favorably to their cancer therapy than patients who underwent these treatments without reishi. Reishi also increased the percentages of several subsets of T cells and may have slightly increased NK cell activity. The authors concluded that reishi could be considered “as an alternative adjunct to conventional treatment in consideration of its potential of enhancing tumour response and stimulating host immunity” (Jin 2012).

Pu-erh Tea Extract

Pu-erh tea, made from select leaves of Camellia sinensis, has a long history of use in ancient Chinese medicine for anti-aging and preventing infections (Lv 2014; Zhang 2012; Chu 2011). Pu-erh tea is rich in polyphenols and other bioactive molecules, including theabrownins, a unique group of compounds developed during the post-fermentation process (Lee 2013). Laboratory, animal, and clinical studies have demonstrated the ability of Pu-erh tea extract to help improve multiple features of immune senescence.

In senescence-accelerated mice (a model for aging), supplementation with Pu-erh tea extract markedly increased fractions of naïve T cells, cytotoxic T cells, and NK cells. In addition, elevated levels of the inflammatory cytokine IL-6 fell by 43%. Based on these results, the authors concluded that long-term consumption of Pu-erh tea may increase resistance to infection and cancer in aging individuals (Zhang 2012).

In a randomized controlled trial in 90 individuals with increased susceptibility to chronic low-level inflammation due to metabolic syndrome, Pu-erh tea extract supplementation plus diet and lifestyle advice was compared with diet and lifestyle advice alone. In the pu-erh tea extract group, levels of the inflammatory markers C-reactive protein, tumor necrosis factor-alpha, and IL-6 significantly decreased, while levels of IL-10, an anti-inflammatory molecule, increased; there were no significant changes in levels of these markers in the group receiving only diet and lifestyle advice (Chu 2011; Moore 2001).

In a laboratory study, Pu-erh tea inhibited proliferation and induced programmed cell death (apoptosis) in cancer cells. In an animal component of this study, mice treated with Pu-erh tea had reduced tumor volumes and fewer lymph node metastases than untreated mice. In addition, levels of IL-6, IL-12, and tumor necrosis factor-alpha were lower in Pu-erh-treated mice than in control mice. In this study, higher doses of pu-erh tea produced greater anti-cancer effects (Zhao 2014).

Enzymatically Modified Rice Bran

Enzymatically modified rice bran, a derivative of rice bran, has been shown to enhance the number and function of immune cells, particularly NK cells (Perez-Martinez 2015; Cholujova 2013; Ghoneum, Abedi 2004; Weiskopf 2009). This specially modified rice bran is a source of the immune-enhancing polysaccharide arabinoxylan (Choi 2014), which has been shown to prevent viral infections of the upper respiratory tract in individuals aged 70 to 95 (Maeda 2004). Polysaccharide fractions of enzymatically modified rice bran have also demonstrated antibacterial and anti-cancer properties (Kim 2007). In fact, several researchers have suggested enzymatically modified rice bran may be beneficial as an adjuvant cancer treatment (Perez-Martinez 2015; Ghoneum, Badr El-Din 2014; Ghoneum 2013).

A series of laboratory and animal experiments showed enzymatically modified rice bran increased the activity of several immune cells including neutrophils, monocytes, macrophages, and dendritic cells (Cholujova 2009; Ghoneum 2011; Ghoneum, Matsuura 2004; Ghoneum 2008; Ghoneum, Agrawal 2014). In a 2013 study on multiple myeloma patients, supplementation with an enzymatically modified rice bran product was shown to increase NK cell activity (Cholujova 2013). Enzymatically modified rice bran also increased susceptibility of cultured breast cancer cells to a chemotherapy agent by over 100-fold (Ghoneum, Badr El-Din 2014).

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is a steroid hormone that plays a major role in healthy immune system functioning (Buford 2008; Weksler 1993). DHEA levels decline markedly with age. By age 80, DHEA levels fall to 10‒20% of their peak values (Kroll 2015; UMMC 2014).

A clinical trial in men with an average age of 63 and low serum DHEA-sulfate (DHEA-S) levels found that DHEA status was rapidly corrected with oral supplementation. Compared with placebo, DHEA treatment resulted in improved immune parameters, including monocyte levels, B- and T-cell function, and NK-cell levels (Khorram 1997). In a small observational study of 38 participants, salivary DHEA levels were positively correlated with salivary bactericidal activity, a measure of innate immune function (Prall 2015). Another observational study noted an association between low levels of DHEA and high levels of IL-6, an inflammatory cytokine implicated in immune senescence. Furthermore, DHEA inhibited IL-6 production by immune cells taken from study participants (Straub 1998; Varadhan 2014). According to a study in aged mice, DHEA may also enhance the immune response to influenza vaccine (Danenberg 1995).

DHEA plays a critical role by serving as a counterweight to cortisol. Cortisol is an adrenal hormone with immunosuppressive properties, while DHEA may have direct immunostimulating properties: in a laboratory study of white blood cells from donors who were at least 65 years old, DHEA treatment reversed the age-related reduction of specific receptors on immune cells and increased immune cell responsiveness (Corsini 2005). Although DHEA levels decline dramatically with age, cortisol levels remain relatively constant, leading to an imbalance of these two hormones that is believed to contribute to immune senescence (Buford 2008; Buoso 2011).

Zinc

Zinc is an essential trace mineral that is critical to healthy immune function. Zinc deficiency is common in older individuals, and causes changes in immune function that resemble those seen in immune senescence (Cabrera 2015; Maywald 2015). Immunological alterations associated with zinc deficiency include diminished thymus function, decreased antibody response to vaccines, and impaired function of phagocytic and NK cells (Haase 2009; Cabrera 2015).

In a study in healthy older volunteers, daily intake of 45 mg zinc for one year resulted in a 67% reduction versus placebo in incidence of infections. Levels of tumor necrosis factor-alpha, an inflammatory cytokine, were also greatly reduced in those taking zinc (Prasad 2007). In a study of older individuals in nursing homes, residents with normal zinc levels had a significantly lower incidence of pneumonia compared with zinc-deficient individuals. Zinc-replete individuals also had shorter pneumonia duration and 50% lower usage of antibiotics, as well as lower all-cause mortality (Meydani 2007). A controlled clinical trial in aged individuals showed supplementation with 45 mg zinc per day for six months decreased plasma markers of inflammation, including IL-6 and C-reactive protein (Bao 2010).

Combining zinc with other important vitamins and minerals may also aid immune function. In a randomized controlled trial that enrolled 42 subjects between 55 and 75 years of age, those who took a multivitamin/mineral supplement containing 10 mg zinc and 1,000 mg vitamin C, along with other vitamins and minerals, for 12 weeks experienced fewer self-reported sick days and less severe symptoms than those who took placebo. The number of sick days decreased by nearly 65% with supplement use (Fantacone 2020).

Vitamin E

Sufficient vitamin E is critical for maintaining efficient immune function. In fact, a variety of animal studies have shown vitamin E deficiency can trigger immune suppression. Clinical evidence has shown vitamin E supplementation can increase resistance to infection, especially in older individuals (Wu 2014; Wu 2008; Han 2006).

In a study in elderly men and women, supplementation with 200 mg per day vitamin E significantly enhanced immune parameters including neutrophil, T-cell, B-cell, and NK-cell function, bringing their values close to those of younger healthy adults (De la Fuente 2008).

Increased vitamin E intake has been shown to restore the decline in T-cell function associated with aging. This improvement in T-cell function results from vitamin E’s direct impact on T cells as well as inhibition of prostaglandin E2, a mediator of inflammation and a T-cell suppressor (Wu 2014; Wu 2008; Han 2006). In a mouse model, vitamin E supplementation reversed the age-associated decline in naïve T-cell function (Adolfsson 2001).

Fucoidan

Certain Japanese populations have among the longest life expectancies in the world. Regular consumption of brown seaweed rich in a compound called fucoidan may contribute to their longevity. Studies have shown fucoidan possesses immune-enhancing, anti-inflammatory, antiviral, and anti-tumor properties (Jin 2014; Negishi 2013; Kyung 2012; Lee 2015).

Evidence from a 2014 laboratory and animal study indicates fucoidan may induce anti-tumor immune activity and increase the effectiveness of an experimental anti-tumor vaccine. Based on their findings, the study authors suggested fucoidan may be useful as a component of anti-cancer vaccines in the future (Jin 2014).

In a study in elderly Japanese volunteers, fucoidan supplementation was found to increase the immune response to the seasonal influenza vaccine. Compared with a placebo group, volunteers taking fucoidan had higher influenza virus-specific antibody levels and increased NK-cell activity five weeks after receiving the flu vaccine. These findings suggest fucoidan may reduce incidence of infection and prevent serious health problems in aging individuals with poor immune function by increasing vaccine effectiveness (Negishi 2013).

Tinospora cordifolia

Tinospora cordifolia (T. cordifolia), a medicinal herb used in traditional Ayurvedic medicine, has been the subject of considerable scientific research. Several chemical constituents that enhance immune function have been isolated from T. cordifolia (Aranha 2012; Sharma 2012; Bala, Verma 2015; Bala, Pratap 2015).

The polysaccharides from T. cordifolia are of particular interest. One of these complex carbohydrates, an arabinogalactan, has been shown to enhance dendritic cell maturation and the ability of these cells to kill cancer cells. Another T. cordifolia polysaccharide, an alpha-glucan, demonstrated the ability to activate NK cells, B cells, and T cells, eliciting a dose-dependent increase in their tumor cell-killing function (Nair 2004; Pandey 2014).

Animal and clinical studies have demonstrated T. cordifolia’s powerful immune effects in a range of conditions. In a randomized clinical trial in surgical patients with suppressed immune function, half received usual care alone while half received usual care plus T. cordifolia supplements. Neutrophil function normalized in the T. cordifolia recipients but not in controls. Septicemia, an infection in the bloodstream and a serious complication of surgery, was evident in 50% of controls but in none of those who received T. cordifolia (Rege 1993). In rats, T. cordifolia decreased arthritic inflammation and bone and cartilage damage, and also reduced levels of inflammatory cytokines, including tumor necrosis factor-alpha and IL-6 (Sannegowda 2015).

N-acetylcysteine

N-acetylcysteine (NAC) is a form of the sulfur-containing amino acid cysteine, which is a precursor of glutathione, an important facilitator in metabolic detoxification (Brosnan 2006; Santus 2014; Millea 2009). Glutathione plays a critical role in regulating inflammatory responses, particularly in the lungs. It is essential for some immune functions, including proliferation of T cells and the cell-killing activity of neutrophils and dendritic cells. Decreased cellular levels of glutathione are linked to increased susceptibility to infection (Ghezzi 2011).

In a controlled clinical trial in 262 individuals at high risk of influenza (flu) and flu-like illness, NAC supplementation at a dosage of 600 mg twice daily for six months resulted in a significant decrease in frequency and severity of flu and flu symptoms, such as cough, sore throat, headache, and muscle and joint pain. NAC’s ability to protect against flu symptoms was especially evident during the winter season. Of those who tested positive for influenza virus infection during the study, only 25% in the NAC group developed symptomatic illness compared with 79% in the placebo group (De Flora 1997). This same NAC dosage in dialysis patients, over eight weeks, resulted in marked reductions in levels of inflammatory markers, including C-reactive protein, tumor necrosis factor-alpha, and IL-6 (Purwanto 2012).

Andrographis paniculata

Andrographis paniculata is a traditional Chinese medicinal plant used to treat infection, colds, fever, and inflammation. In a 2010 study in tumor-bearing mice, Andrographis paniculata and one of its active constituents, andrographolide, enhanced the ability of NK cells and other immune cells to destroy cancer cells (Sheeja 2010; Ji 2005).

Reduced vaccine effectiveness is a prominent feature of immune senescence (Goronzy 2013; Grubeck-Loebenstein 2009; McElhaney 2012), and evidence suggests Andrographis paniculata may improve immune response to vaccines. In a study in mice, oral Andrographis paniculata extract and andrographolide both enhanced antibody production and activated immune cells in response to a Salmonella vaccine (Xu 2007).

Beta-Glucan

Beta-glucans are polysaccharides (carbohydrates) found in the cell walls of bacteria, fungi, grains including oats, and algae. Beta-glucans are among the active ingredients responsible for the immune modulating benefits of medicinal mushrooms such as reishi (Chan 2009; Karumuthil-Melethil 2014; Aleem 2013).

Beta-glucans have been found to modulate multiple aspects of immune activity, with notable anti-tumor and antimicrobial properties (Vannucci 2013; Chen, Seviour 2007; Dalonso 2015). A 2013 review of studies found plant extracts containing beta-glucans improve survival rates and quality of life in cancer patients. This review also found that beta-glucan extracts reduced side effects of chemotherapy and radiotherapy in several different forms of cancer (Aleem 2013).

Tumor cells evade the immune system through mechanisms that suppress immune function and induce immune tolerance (Liu 2009). One study showed beta-glucan may help overcome this barrier to cancer cell elimination by decreasing the suppressive function of regulatory immune cells that have been affected by tumor signaling (Ning 2016).

Lactoferrin

Lactoferrin is an iron-binding protein found in body secretions including breast milk, saliva, tears, nasal secretions, and intestinal fluids, as well as in neutrophils. Lactoferrin’s antibacterial effects include damaging microbial cell membranes and binding and isolating iron, which is needed by nearly all bacteria to grow and thrive (Siqueiros-Cendon 2014; Legrand 2008). The iron-free form of lactoferrin (apolactoferrin) is a potent iron-binding protein and has been shown to have antibacterial effects (Siqueiros-Cendon 2014; Zakharova 2012; Luna-Castro 2014; Dionysius 1993).

Lactoferrin possesses direct antimicrobial activity against a wide variety of microorganisms including bacteria, viruses, fungi, and parasites (Siqueiros-Cendon 2014; Legrand 2008; Valenti 2005; Caccavo 2002). In an animal study, 69% of mice pretreated with intravenous lactoferrin survived for 30 days after being given a lethal dose of toxic E. coli bacteria, whereas only 4% of control mice survived (Zagulski 1989).

Vitamin C

Vitamin C supports the function of both the innate and adaptive immune systems and plays an important role in the defense against bacteria and viruses. In addition to stimulating immunity, vitamin C also appears to restrain excessive immune activity, perhaps in part by interfering with the synthesis of inflammatory cytokines (Sorice 2014; Pohanka 2012; Holmannova 2012).

Emerging evidence suggests vitamin C supplementation may help maintain immune function as we age. In a mouse model of vitamin C deficiency and premature aging, a higher dose of supplemental vitamin C (equivalent to about 1300 mg per day in a 175 lb person) was compared with a lower dose (equivalent to about 130 mg per day in a 175 lb person). After one year, mice receiving the higher dose of vitamin C exhibited better thymus gland preservation and greater immune cell counts than mice receiving the lower dose (Uchio 2015).

Results from a large analysis of placebo-controlled trials indicate vitamin C supplementation reduces the duration of colds, with an 8% reduction in adults and a 14% reduction in children. In addition, the analysis found vitamin C supplements reduced the incidence of colds by half in people undergoing extreme physical exertion, such as marathon runners (Hemila 2013).

Whey Protein

Whey is the liquid separated from the curds during the cheese making process. Products derived from whey have demonstrated immune-modulating properties (Krissansen 2007; Rusu 2009). Whey protein is especially rich in precursor amino acids involved in the synthesis of glutathione, a powerful free radical scavenger with anti-inflammatory properties. Glutathione is essential for both innate and adaptive immunity (Krissansen 2007; Kloek 2011; Kent 2003; Micke 2001). (N-acetylcysteine, described earlier, is also a glutathione precursor.)

A pilot study compared the effects of whey protein and soy protein on vaccine responsiveness in 17 healthy senior citizens (Freeman 2010). The participants were randomly assigned to consume either whey protein or soy protein for four weeks. They then received the pneumococcal vaccine and continued protein supplementation for four weeks after vaccination. Compared with those who received soy protein, people who received whey protein exhibited a more robust antibody response to 12 of 14 types of pneumococcal bacteria, including the four most harmful bacterial types. The investigators concluded, “ Whey protein supplementation is a promising supplement to stimulate the immune response to vaccine in senior citizens and possibly to counteract [immune senescence] while larger studies are warranted.”

In another clinical trial in 12 healthy volunteers, a single dose of a whey extract was a more effective immune activator than placebo, rapidly increasing phagocytic (microbe-engulfing) activity of certain immune cells and mobilizing new NK cells into circulation (Jensen 2012). In a study in cultured neutrophils, whey protein extract had no immediate effect but instead had a priming effect, heightening neutrophil activity 24 hours later (Rusu 2009).

Garlic Extract

Garlic, well known for its ability to improve cardiovascular risk factors, also has immune-modulating and immunostimulatory properties, as well as anti-tumor effects (Ebrahimi 2013; Purev 2012; Kyo 2001).

A detailed review of data from published clinical trials found garlic supplements significantly reduce the number, duration, and severity of upper respiratory tract infections. This review also found garlic supplements stimulate immune function by increasing macrophage activity, numbers of NK cells, and production of T and B cells (Ried 2016). In a clinical trial, 120 healthy participants, 21–50 years old, were assigned to use 2.56 g aged garlic extract or placebo daily for 90 days during cold and flu season. Garlic supplementation was associated with reduced cold and flu severity, as well as increased cytotoxic T-cell and NK-cell proliferation and activity (Percival 2016). In animal research, garlic has been shown to increase antibody production and enhance the cell-killing activity of macrophages, cytotoxic T cells, and NK cells (Ghazanfari 2000). Other animal research suggests aged garlic extract may prevent immune suppression associated with psychological stress (Kyo 1999).

Interestingly, garlic has also been demonstrated to suppress the overactive immune response associated with allergic reactions. Data from experimental studies indicate aged garlic extract may reduce histamine release and modify the function of immune cells involved in allergic reactions (Kyo 2001).

Apigenin

Apigenin is a flavonoid found in fruits, vegetables, and herbs, including parsley, celery, onions, oranges, chamomile, thyme, and tea. As with other flavonoids, apigenin has been shown to have anti-inflammatory and antiapoptotic effects (eg, in heart cells temporarily deprived of oxygen) (Salehi 2019; Zhou 2018). In a study on collagen-producing cells called fibroblasts, apigenin reversed the effects of pharmacologically induced senescence by reducing the cells’ pro-inflammatory characteristics (Lim 2015). Furthermore, apigenin has been shown to decrease the risk of ultraviolet-induced senescence of collagen-producing cells in the laboratory. When topically applied to aging skin, apigenin was associated with improvements in skin elasticity, fine wrinkles, skin evenness, and moisture content (Choi 2016). In mice, the anti-aging properties of apigenin were shown to be attributable in part to modification of gene expression (Sang 2017).

Interestingly, the effects of apigenin appear to differ in normal cells versus cancer cells. In normal fibroblasts, apigenin reduces senescent characteristics. In a study on breast cancer cells, apigenin decreased the invasiveness and aggressiveness of the cells (Perrott 2017). Furthermore, apigenin was shown to increase the sensitivity of glioblastoma cells to apoptosis by inducing cell senescence (Dixit 2012).

Fisetin

Fisetin is a flavonoid found in fruits and vegetables (particularly strawberries, apples, and persimmons) (Grynkiewicz 2019). In preclinical models, fisetin has been shown to extend the lifespan of a wide variety of species, including nematodes, fruit flies, and mice (Wood 2004; Yousefzadeh 2018). In mice aged 85 weeks (equivalent to approximately 75 years in humans), administration of a diet supplemented with fisetin extended both median and maximal lifespan compared with a control diet (Yousefzadeh 2018).

Fisetin supplementation is believed to specifically induce cell death in senescent cells but not dividing cells through complex signaling pathways (Wood 2004; Zhu 2017). Fisetin activates sirtuins, which are proteins that play critical roles in DNA repair and aging. Sirtuin activation also plays a role in the longevity-promoting benefits of caloric restriction, which has been shown in preclinical studies to extend the lifespan of many organisms (Wood 2004). Fisetin has also been shown to reduce inflammatory signaling, decrease oxidative stress, and exert neuroprotective effects (Singh 2018; Jia 2019). In aging mice, fisetin supplementation decreased cognitive deficits (Currais 2018). The benefit of supplemental fisetin for reducing inflammation and frailty in elderly adults is currently under investigation in the AFFIRM-LITE clinical trial (Kirkland 2020).

2021

Apr: Updated section on chronic viral infections in How Aging Accelerates Immune Decline

2016

Dec: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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Immune Senescence

Immune Senescence

1 Overview

Summary and Quick Facts for Immune Senescence

How Aging Accelerates Immune Decline

Novel and Emerging Interventions

Diet and Lifestyle Considerations

Integrative Interventions

2 Introduction

3 Understanding The Immune System

Innate Immune System

Adaptive Immune System

Microbiota and Immunity

4 How Aging Accelerates Immune Decline

Decline in Naïve T Cells

Increasing Numbers of Senescent Memory T cells

Decrease in Functional Natural Killer Cell Activity

Thymus Gland Atrophy

Cimetidine and the Immune System

Overproduction of Interleukin-6

Chronic Viral Infection and Immune Senescence

5 Assessing Immune Function

6 Novel And Emerging Interventions

Parabiosis and Immune Function

Granulocyte-colony Stimulating Factor

Senolytic Activators

7 Diet and Lifestyle Considerations

Caloric Restriction

Mediterranean Diet

Exercise

Stress Management

Sleep

8 Nutrients

Cistanche

Reishi

Pu-erh Tea Extract

Enzymatically Modified Rice Bran

Dehydroepiandrosterone (DHEA)

Zinc

Vitamin E

Fucoidan

Tinospora cordifolia

N-acetylcysteine

Andrographis paniculata

Beta-Glucan

Lactoferrin

Vitamin C

Whey Protein

Garlic Extract

Apigenin

Fisetin

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2016

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References

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