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Aging and the Immune System
By the year 2050, 25 percent of the population of the United States will be 60 years of age or older. Thus, this age is a theoretical limit to a healthy human lifespan.
Thymic involution has been observed in all vertebrate species that have a thymus gland. Animal studies have shown that transplanted thymic grafts between inbred strains of mice involuted according to the age of the donor and not of the recipient, implying the process is genetically programmed. There is evidence that the thymic microenvironment, so vital to the development of naïve T cells, loses thymic epithelial cells according to the decreasing expression of the FOXN1 gene with age.
It is also known that thymic involution can be altered by hormone levels. Sex hormones such as estrogen and testosterone enhance involution, and the hormonal changes in pregnant women cause a temporary thymic involution that reverses itself, when the size of the thymus and its hormone levels return to normal, usually after lactation ceases. What does all this tell us? Can we reverse immunosenescence, or at least slow it down? The potential is there for using thymic transplants from younger donors to keep thymic output of naïve T cells high. Gene therapies that target gene expression are also seen as future possibilities. The more we learn through immunosenescence research, the more opportunities there will be to develop therapies, even though these therapies will likely take decades to develop. The ultimate goal is for everyone to live and be healthy longer, but there may be limits to immortality imposed by our genes and hormones.
Preventing COVID-19 and aging: Geroprotector to enhance resilience and vaccine response
IMAGE: randomized clinical trial for prevention of COVID-19 by rapamycin would likely involve transient rapamycin treatment with rapamycin in older (selectively enrolled if estimated biological age exceeds their chronological age). view more
Credit: Deep Longevity Limited
10th of February, Wednesday, Hong Kong - Deep Longevity, a fully-owned subsidiary of Regent Pacific (SEHK:0575.HK), specializing in the development and the application of next-generation artificial intelligence (AI) for aging and longevity research, today announced the publication of an article in Lancet Healthy Longevity titled "The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19".
While the pandemic continues to unfold, targeted therapeutic solutions for COVID-19 are still not established. The extremely rapid development of various vaccines as a preventative approach provides reassurance, but at the same time faces a number of major challenges: insufficient protection against mutated variants, production line limitations, anti-vaccination skeptics etc. At the same time, COVID-19 still disproportionately affects older and comorbid individuals, who mostly suffer from more severe courses of illness, complications and lethal outcomes. Most frequently, advanced age goes hand in hand with comorbidities, which potentiates the adverse effect of the virus drastically.
Vaccines are still far from arriving at a complete protection. Unfortunately, the population least likely to benefit from such solutions are also those at the highest risk: the elderly and individuals with pre-existing age-related conditions. "It is a double-edged sword: the immune system of elderly and multimorbid (any age) patients is compromised. Those individuals are thus more prone to get infected and to develop a more severe disease. On the other hand, their response to a vaccine - which acts on and with the immune system - might be insufficient. We also see reinfections occurring in elderly patients, which then take an even more aggressive course, leading to fatalities." said associate prof. Evelyne Bischof, Harvard, Columbia and Basel trained MD, practicing physician, one of the authors of the paper in Lancet Healthy Longevity today - a joint work of the world-renowned biogerontologists and longevity specialists prof. Alex Zhavoronkov, prof.Matt Kaeberlein, and prof. Richard Siow. 'It is a major problem not only because of the predominantly aged demographics, increased danger in care homes for elderly, but especially because most elderly patients are also comorbid - due to the aging processes causing age-related, mostly chronic diseases." She continues. Such patients are at a significantly enhanced risk of infection and death if they need to be hospitalized for non-COVID-19 reasons.
While most trials exclusively target the infectious component of the disease, the authors outline the rationale behind a double approach: targeting COVID in the biologically aged for better prevention, vaccination efficacy and improved outcomes. The reasoning is complex and interrelated: old age is related with immunosenescence (immune system aging and thus worse function), with age-related diseases that are related with more severe COVID-19 course, e.g. diabetes, hypertension, cancer etc., with frailty and vulnerability (more exposure, e.g. due to homecare or institutionalization). Therefore, in order to efficiently intervene, geroprotective and senoremediative interventions towards mounting the immune response to vaccines are of uttermost importance, both from the medical, as well as the global economic aspect.
AI-based strategies were harnessed for repurposing known geroprotectors such as rapamycin, for the prevention of SARS-CoV-2 infection. Pre-clinical simulation analysis and previous evidence showing paradoxical immunopotentiation effects of rapamycin urge to propose additional clinical trials for these molecules in the broad elderly population.
In addition, in contrast to current studies, the authors propose to use an objective measurement of the biological rather than the chronological age. In the absence of reliable predictive and prognostic COVID19-biomarkers, minimally-invasive deep aging clocks are suggested as surrogate markers of biological age to track the efficacy of these preventative geroprotective interventions and to stratify the patients by predicted severity of the disease. Moreover, it will allow validation of markers of biological age in the context of viral infections and identification mechanisms by which geroprotectors enhance resilience against infections and reduce the severity of symptoms. This AI based approach in precision medicine was just recently illustrated in Nature Aging
The Lancet Healthy Longevity paper outlined the available evidence and a clinical translation of the geroprotector rapamycin for further research in a clinical trial setting, paving a new perspective: longevity medicine in pandemics. Longevity medicine as AI-based precision medicine aims to assure a healthy lifespan, mitigating and eliminating the risks and development of age-related diseases. Different from the reactive medicine, it uses the latest anticipatory technologies and muti-omics technologies to delay, attenuate or reverse senescence on all levels (cellular, tissue, system, organism, society). The benefits of such an approach in this and future pandemics is obvious, while the publication pioneers the scientific base for a longevity medicine RCT using geroprotective interventions.
Originally incubated by Insilico Medicine, Deep Longevity was acquired on 14 December 2020 by Regent Pacific Group Limited (SEHK:0575.HK), a specialist healthcare, wellness and life sciences investment group. Deep Longevity is developing explainable artificial intelligence systems to track the rate of aging at the molecular, cellular, tissue, organ, system, physiological, and psychological levels. It is also developing systems for the emerging field of longevity medicine, enabling physicians to make better decisions on the interventions that may slow down or reverse the aging processes. Deep Longevity developed the Longevity as a Service (LaaS) solution to integrate multiple deep biomarkers of aging dubbed "deep aging clocks" to provide a universal multifactorial measure of human biological age.
https:/ / deeplongevity. com/
About Regent Pacific (SEHK:0575.HK)
Regent Pacific is a diversified investment group based in Hong Kong currently holding various corporate and strategic investments focusing on the healthcare, wellness, and life sciences sectors. The Group has a strong track record of investments and has returned approximately US$298 million to shareholders in the 21 years of financial reporting since its initial public offering.
https:/ / www. regentpac. com/
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Keywords: stress protein, cell stress, psychological stress, heat shock (stress) proteins, unfolded protein response (UPR)
Citation: Bae Y-S, Shin E-C, Bae Y-S and Van Eden W (2019) Editorial: Stress and Immunity. Front. Immunol. 10:245. doi: 10.3389/fimmu.2019.00245
Received: 22 August 2018 Accepted: 28 January 2019
Published: 14 February 2019.
Edited and reviewed by: Pietro Ghezzi, Brighton and Sussex Medical School, United Kingdom
Copyright © 2019 Bae, Shin, Bae and Van Eden. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
As people age, the immune system becomes less effective in the following ways:
The immune system becomes less able to distinguish self from nonself (that is, to identify foreign antigens). As a result, autoimmune disorders become more common.
Macrophages (which ingest bacteria and other foreign cells) destroy bacteria, cancer cells, and other antigens more slowly. This slowdown may be one reason that cancer is more common among older people.
T cells (which remember antigens they have previously encountered) respond less quickly to the antigens.
There are fewer white blood cells capable of responding to new antigens. Thus, when older people encounter a new antigen, the body is less able to remember and defend against it.
Older people have smaller amounts of complement proteins and do not produce as many of these proteins as younger people do in response to bacterial infections.
Although the amount of antibody produced in response to an antigen remains about the same overall, the antibodies become less able to attach to the antigen. This change may partly explain why pneumonia, influenza, infective endocarditis, and tetanus are more common among older people and result in death more often. These changes may also partly explain why vaccines are less effective in older people and thus why it is important for older people to get booster shots (which are available for some vaccines).
These changes in immune function may contribute to the greater susceptibility of older people to some infections and cancers.
Changes to the adaptive immune system with age have a clear impact on immune cell function, and it is well-documented that older adults are more susceptible to infections and suffer more long-term complications as a result [9, 10]. Furthermore, vaccine responses are typically diminished in older individuals, resulting in lower antibody titers and reduced efficacy [11,12,13,14]. Multiple studies have established correlations between dysregulation in the adaptive immune system and negative clinical outcomes, but a detailed mechanistic understanding of how these changes in adaptive immune cell function affect responses to disease and/or vaccination is lacking. We focus our subsequent discussion on the relationship between observed differences in immune cell function and the pathology of infectious diseases that disproportionately affect the elderly, as well as research efforts in vaccinology that have been aimed at improving immune responses in older adults.
Influenza virus is one of the leading causes of respiratory infections among older adults. An estimated 50–70% of influenza-related hospitalizations impact adults over the age of 65 each year, with 70–90% of deaths related to influenza occurring among this same age group . Numerous studies have reported influenza vaccine efficacy to be significantly lower in older adults compared to younger subjects, although there is some debate regarding how these statistics are reported [116, 117]. Nevertheless, the documented burden of influenza infection on the elderly population, combined with known deficiencies in vaccine-induced immune responses, emphasizes the need to understand the mechanisms governing adaptive immunosenescence as they relate to influenza-specific immune outcomes.
Humoral immunity is known to play an important role in preventing influenza virus transmission and infection, yet antibody responses have been shown to decline with age. A greater number of older adults fail to seroconvert (i.e., fourfold increase in post-vaccination antibody titer) relative to their younger counterparts, with seroconversion rates ranging from 10 to 30% in older adults compared to 50–75% in younger individuals [16, 118]. Recent evidence has suggested this decline in vaccine-induced humoral immunity is due to reduced neutralizing antibody production rather than a decline in total IgG output , and multiple studies have demonstrated that older adults fail to generate protective hemagglutination inhibition (HAI) antibody titers compared to younger adults following vaccination [16, 119]. Furthermore, older adults exhibit reduced diversity in their antibody repertoire following influenza vaccination, although a subset of elderly vaccine responders generate broadly cross-reactive antibodies that recognize multiple influenza strains . The route of exposure may also be a key mediator of antibody responses, as differences have been observed between subjects naturally infected through the mucosal surfaces of the respiratory tract and those receiving intramuscular vaccinations . Collectively, these findings are consistent with declining B cell function, but none have been mechanistically linked with negative clinical outcomes.
Cellular immunity is also strongly associated with protection against influenza, as some older adults have been shown to remain protected against infection even in the absence of robust antibody responses . Declining T cell responses to influenza have been observed in both murine and human studies, suggesting age-related dysregulation in the T cell compartment may play a role in disease susceptibility. Studies have shown that older subjects experience altered frequencies of influenza-specific memory CD4 + T cell subsets post-vaccination relative to younger subjects , and these population shifts may alter the ability of memory T cells to effectively traffick to the lung in response to infection. Interestingly, studies in aged mice revealed that, although the total number of CD4 + T cells responding to infection in the lung did not differ from those in younger mice, there was a distinctive reduction in Th1 cells secreting inflammatory cytokines . While deficiencies in CD4 + T cell responses could certainly impact the development of protective immunity, alterations in CD8 + T cells are equally important. Aged mice exhibit limited diversity in their TCR repertoire compared to younger mice, which decreases the magnitude of their response to the immunodominant influenza nucleoprotein epitope NP366–374 . Although difficult to examine in humans due to the heterogeneity of responses , clonal expansion of CD45RA + CD28 − CD8 + effector T cells has been implicated in causing Th1/Th2 cytokine imbalances that inhibit productive antibody responses . Evidence from human studies also indicates that CD8 + T cell effector function is decreased following vaccination , although studies in mice indicate that decreased numbers of influenza-specific CD8 + T cells rather than functional changes are responsible for declining responses . Collective differences between these reports suggest that CD4 + and CD8 + T cells may be differentially affected by immunosenescence, and further study is warranted in order to fully understand the effects of adaptive immunosenescence on cellular immunity to influenza.
Despite an incomplete mechanistic understanding, older adults are clearly at greater risk of influenza infection, and current evidence suggests this is due to dysregulation of the adaptive immune system. In an effort to improve clinical outcomes following influenza vaccination, vaccine formulations have been licensed specifically for use in the elderly. Fluzone® High-Dose, which contains 60 μg hemagglutinin per viral strain as opposed to 15 μg per strain in the standard dose vaccine, has been widely utilized in older adults and significantly increases humoral responses and efficacy . More recently, the emulsion-based adjuvant MF59® has been added to influenza vaccines (Fluad™) and approved for use . While the mechanisms of action are not completely understood, MF59® is believed to enhance innate immune responses and stimulate germinal center reactions [128, 129]. It should be noted that these two formulations have been globally employed to different degrees. Vaccines containing MF59® have been licensed for use in Europe since 1997  but did not gain approval for use in the US until 2015. Alternatively, Fluzone® High-Dose has been licensed for use in the US since 2009  but only received its first approval for use in Europe (UK) in 2019. Furthermore, these vaccines were not directly engineered to address any known mechanistic deficiencies in aging B cells rather, these formulations advanced through clinical studies due to their overall improvement in vaccine efficacy. Despite their ability to generate higher protective antibody titers in the elderly, the mechanisms by which these two vaccines elicit such robust responses are poorly understood.
Respiratory syncytial virus
Similar to influenza, respiratory syncytial virus (RSV) is another viral respiratory disease that has a disproportionate impact on older adults. Although RSV infection is usually mild in healthy young adults, serious complications can arise in older patients—particularly those with existing co-morbidities, such as chronic obstructive pulmonary disease and cardiovascular disease [131,132,133,134]. RSV infections often result in prolonged hospitalization and are associated with significant mortality rates (12–18%) in the elderly [135, 136]. Despite the impact of RSV on the aging population, the correlates of immunological protection remain poorly understood, although studies have indicated that adaptive immunosenescence may underlie the increased risk of severe disease among the elderly.
T cell responses have been shown to correlate with protection from RSV infection, and dysregulation of cellular immunity has been implicated in disease pathogenesis. Animal studies have shown that memory T cells mediate protection from disease and accelerate viral clearance but can contribute to tissue pathology if there is an imbalance in cytokine signaling [137,138,139,140]. Bias in cytokine production toward a Th2-type response has been noted to occur with age [67, 141], and studies have found that the number of circulating memory CD4 + and CD8 + T cells are also reduced in older adults [142, 143]. Specifically, RSV F protein-specific T cell responses were shown to be deficient in older adults compared to younger individuals . These findings collectively suggest that cellular immunity may play a significant role in RSV pathogenesis, as both diminished and hyperactive responses can promote enhanced disease pathology in the elderly.
Although cellular immunity is predominantly associated with protection from RSV, correlations with humoral immune responses have also been demonstrated. Neutralizing antibody titers, as well as total IgG and mucosal IgA titers, have been associated with protection from RSV infection in adults [144,145,146] however, some studies have reported equivalent neutralizing antibody titers between older and younger subjects, indicating cellular immunity as a stronger determinant of protection with age . In experimental challenge models, mucosal IgA responses have been found to confer greater protection than serum neutralizing antibodies in adults, and deficits in IgA production have also been associated with an increased risk of recurrent RSV infection . In contrast, one study has reported a stronger correlation between neutralizing antibody titer and disease susceptibility in the elderly . While the precise role humoral immunity plays in protection from RSV remains unclear, it is apparent that age-related changes in both humoral and cellular immune responses may impact the progression of RSV infections in older adults.
Despite the apparent burden that RSV places on healthy aging, no vaccine is currently licensed for preventive use against RSV infection. This is an active area of research, as more than 60 vaccine candidates are currently in various stages of development however, those few that have advanced to clinical testing have not demonstrated convincing efficacy . The majority of vaccines in development for older adults are either nanoparticle or subunit-based formulations that primarily target the RSV F protein . Clinical studies have failed to demonstrate improved vaccine efficacy despite showing robust immunogenicity, and insight into structural changes of the F protein may inform the design of new vaccine candidates. Studies have shown that vaccines using stabilized pre-fusion F protein generate higher neutralizing antibody titers compared to formulations containing post-fusion F protein [149, 150]. Furthermore, as described above, immunosenescence has been demonstrated to affect many of the factors directly associated with protection (memory T cell number and cytokine secretion patterns). This suggests that older adults may benefit from RSV vaccines specifically engineered to maximize immune responses despite immunosenescence – much like has been done with influenza. Consequently, research efforts to gain a fundamental understanding of RSV immunology in older adults are undoubtedly needed and will serve to inform the design of next-generation vaccines tailored for use in the elderly.
Bacterial pneumonia is another common respiratory disease that is often deadly among older adults. Disease results from infection with Streptococcus pneumoniae, a common bacterial commensal that frequently (albeit transiently) colonizes the upper respiratory tract [151, 152]. While colonization is usually benign, migration or aspiration of S. pneumonia into the lower respiratory tract often results in pronounced disease progression [151, 152]. Mortality rates associated with pneumococcal disease range from 15 to 30% among the elderly , and with the increasing population of older adults, the number of hospital admissions related to pneumococcal pneumonia among adults > 65 years of age has been projected to increase by 87% . Despite the growing disease burden, relatively few mechanistic studies of immunosenescence and pneumococcal immune responses have been conducted, although there has been significant progress made in the development of pneumococcal vaccines for older adults [153,154,155].
Humoral immunity is thought to play a key role in limiting the severity of pneumococcal disease, as deficiencies in either mucosal or systemic antibody production have been associated with poor medical outcomes [156, 157]. Serum IgG antibodies against S. pneumoniae have been identified as critical for preventing invasive bacteremia, while secretory IgA serves to mediate clearance of bacteria from the lung mucosa. Studies investigating the effects of aging on IgA responses in humans are scarce, but studies in mice have found IgA production following intranasal vaccination to be severely limited with age [158, 159]. Human studies have found that older adults (> 65 years of age) have significantly lower IgG antibody titers against many of the common pneumococcal serotypes compared to younger adults, suggesting that antibody titers wane over time [160,161,162]. Additionally, several studies have shown that antibodies from older adults have diminished opsonization activity against S. pneumoniae compared to those from younger adults, indicating there may also be functional deficiencies in antibody responses against pneumococcal antigens [17, 18].
While humoral immunity is primarily thought to mediate protection from disease, there are also important aspects of cellular immunity to consider. CD4 + T cells secreting IL-17 have been identified as key mediators of adaptive immune responses against S. pneumoniae , yet there are conflicting reports regarding age-related changes of T cell responses against pneumococcal infection. A study by Meyer and coworkers identified a significant increase in the percentage of CD4 + T cells in the lungs of older adults , while a separate study found no significant differences in the percentage of cytokine-secreting cells following stimulation with pneumococcal protein antigens . Studies in mice have shown that CD4 + T cell responses can be generated by mucosal vaccination, but substantially more antigen is required to elicit responses in aged mice . More studies are clearly needed in order to inform our understanding of mucosal immunology and aid the design of next generation vaccines against pneumococcal disease.
Two vaccine formulations have been currently licensed for clinical use against pneumococcal disease in older adults: a 23-valent carbohydrate vaccine (Pneumovax® 23) and a 13-valent glycoconjugate vaccine (Prevnar 13®) [165, 166]. Carbohydrate vaccines are poorly immunogenic as they do not inherently stimulate T cell responses, but Prevnar 13® overcomes this limitation via conjugation of the pneumococcal glycans to diphtheria toxoid . In a randomized clinical trial, adults receiving the conjugate vaccine were found to suffer significantly fewer incidences of pneumococcal pneumonia (45% efficacy against non-invasive community-acquired pneumonia
75% efficacy against invasive pneumococcal disease) compared to subjects receiving a placebo . Current evidence suggests an initial immunization with Prevnar 13® followed by subsequent immunizations with either vaccine provides the strongest antibody response , although there are still limitations to this approach. Serotypes excluded from the vaccine formulations can still lead to natural infections, leading to disease despite immunity against other serotypes. Further, comparative studies of the two vaccine formulations in older adults are lacking. Systems immunology studies comparing the responses to these two vaccines will serve to greatly increase our understanding of carbohydrate immunology and the immune response against pneumococcal disease.
Although distinct from respiratory infections, herpes zoster (HZ) is another viral disease that manifests with age, and its pathology is strongly associated with declining cellular immunity. Nearly 100% of the adult population is exposed to varicella zoster virus (VZV) during their lifetime, which establishes latent infection within the dorsal root ganglia . Reactivation of VZV infection is believed to be controlled by cellular immunity, but failure of the T cell compartment to maintain control of the infection with increasing age has been associated with the onset of HZ [12, 170]. This leads to an estimated 1 million cases of HZ in the United States annually that can severely impact the quality of life for older adults often due to complications with postherpetic neuralgia (PHN) . Vaccine development efforts have proven effective in combating HZ in older adults, and efficacy studies have begun to simultaneously provide insight into the immunological mechanisms governing protection against HZ [172,173,174].
Two vaccine formulations have been licensed for clinical use against HZ, but the immunological responses between the two vaccines have been shown to differ significantly. The live attenuated zoster vaccine (Zostavax®) was the first to be approved for use in older adults, and early clinical studies demonstrated improved VZV-specific cellular immune responses despite limited efficacy (
51%) in adults over 60 years of age [175, 176]. Unfortunately, efficacy was found to significantly decline as age at the time of vaccination increased, decreasing to 41% in adults > 70 years of age and 18% in individuals > 80 years of age . Protective immunity has also been shown to wane in the 6–8 years following receipt of the vaccine [12, 13]. As an alternative, a recombinant subunit vaccine (Shingrix™), consisting of recombinant glycoprotein E (gE) and the AS01B adjuvant, was recently approved for use in older adults . Following a two-dose schedule, the recombinant vaccine was found to have markedly improved efficacy (97%) in adults irrespective of age [172, 173]. Furthermore, protective immunity has been found to persist for close to a decade following the initial immunizations [30, 178]. The superior performance of the recombinant vaccine has been attributed to the development of robust gE-specific memory Th1-type responses, which are significantly lower in subjects receiving the live attenuated vaccine [174, 179]. Although the mechanisms governing these differences are not well understood, studies in mice have shown that the AS01B adjuvant stimulates activation of antigen-presenting cells and macrophages in the draining LN .
Contributions from humoral immunity toward protection from HZ have been less well-defined, although a four-fold increase in VZV-specific antibody titers has been proposed as a correlate of protection for Zostavax® [181, 182]. Few studies have investigated specific aspects of humoral immunity against VZV, as evidence from the aforementioned clinical studies clearly implicates cellular immunity as a key determinant of disease protection. A recent study analyzing the functionality of antibodies following immunization with the live attenuated vaccine found that gE-specific memory B cell responses dominated, but these antibodies were unable to neutralize VZV in the absence of complement proteins or prevent the spread of the virus between cells in vitro . These observations continue to suggest that antibody responses do not play a significant role in protective immunity against HZ, but studies investigating humoral immune response following administration of the recombinant vaccine are still lacking. Further studies of these two vaccines are warranted in order to fully elucidate the immunological mechanisms that govern durable protection against HZ.
Ageing is caused by a discreet set of biological mechanisms that can be targeted therapeutically as a new way to treat ageing-related conditions. 17 One of the best validated mechanisms underlying ageing biology is the activity of the protein kinase mTOR. Inhibition of mTOR has been shown to extend lifespan and to improve the function of ageing organ systems, including the immune system, in multiple preclinical species. 18 , 19 The purpose of our trials was to investigate whether targeting ageing biology with mTOR inhibitors could improve immune function and decrease the incidence of RTIs in older adults at doses that were well tolerated. The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years, increased expression of IFN-stimulated antiviral genes in peripheral blood, and decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint), but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).
Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials. In the phase 2b trial, respiratory illness symptoms were collected during twice weekly telephone calls with patients and the primary endpoint required predefined symptomatic criteria to be met as well as laboratory confirmation of an infection. In the phase 3 trial, respiratory illness symptoms were collected in eDiaries that patients filled out each evening and the primary endpoint was based on symptoms alone without requiring laboratory confirmation of an infection. Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI. Thus, the occurrence of respiratory symptoms that have non-infectious causes in older adults such as allergies or underlying cardiopulmonary disease might have contributed to the negative result of the phase 3 trial. In support of this hypothesis, RTB101 was also associated with a greater reduction in the incidence of laboratory-confirmed RTIs than the incidence of RTIs diagnosed solely on the basis of respiratory symptoms in the phase 2b trial. Because RTB101 upregulates antiviral gene expression, RTB101 is only likely to reduce the incidence or severity of respiratory symptoms due to viral infections. Laboratory confirmation of an infection might need to be added as a component of the primary endpoint in future trials of therapies like RTB101 that enhance antiviral immune responses in older adults.
Also, upregulation of antiviral gene expression by RTB101 possibly has treatment benefit in only a subset of older adults or a subset of patients with viral infections. The phase 3 trial enrolled a healthier population than that of the phase 2b trial and the healthier adults might have had less attenuation of their type 1 IFN responses and, therefore, obtained less benefit from upregulation of IFN responses by RTB101. Future trials might benefit from the development of biomarkers that identify older adults with deficient IFN responses or at increased risk of RTIs. The results of the phase 2b and phase 3 trials also raise the possibility that RTB101 decreases the incidence or severity of RTIs caused by only a subset of viruses such as coronaviruses that inhibit the host IFN response. To further address this possibility, trials are underway to investigate whether RTB101 prophylaxis decreases the severity of laboratory-confirmed COVID-19 in adults aged at least 65 years.
Of interest, in the phase 2b trial RTB101 was associated with a significant reduction in the incidence of laboratory-confirmed RTIs with severe symptoms. Thus, upregulation of IFN-induced antiviral immunity by RTB101 might have a greater effect on the severity than the incidence of RTIs. Last, the upregulation of antiviral gene expression by RTB101 might be insufficient to decrease the incidence of viral RTIs and the positive results in the phase 2b trial were a result of type 1 error. Arguing against this possibility is the fact that not only in the phase 2b trial but also in two previous phase 2a trials, 10 , 20 older adults treated with low doses of mTOR inhibitors reported fewer self-reported RTIs than older adults treated with placebo did.
Despite the negative phase 3 results, important lessons were learned from this clinical development programme that is the largest to date targeting ageing biology in humans. First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults. Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses). Further refinement of clinical endpoints and more precise identification of responder patient populations will be important in future trials of therapies that intervene in ageing biology to improve immune function in older adults.
Immune senescence, or the aging of the immune system, particularly its effect on changes in lymphocyte development and function, predisposes older adults to a higher risk of latent virus reactivation. The varicella-zoster virus, for example, the agent responsible for chickenpox in children, remains dormant in nerve cells in the trigeminal and dorsal root ganglia and reactivates in later life to cause shingles and post-herpetic neuralgia.
Other persistent viral infections include Epstein-Barr virus, herpes simplex virus-1 and -2, and cytomegalovirus (CMV).
Age-related immune senescent remodeling likely involves both the innate and adaptive immune system and may contribute to the immune system’s functional decline chronic inflammatory state and risk for frailty, chronic disease, and functional decline in older adults.
Covid-19 and Immunity in Aging Populations — A New Research Agenda
The race is on throughout the world to develop Covid-19 vaccines and therapeutics and end a pandemic that threatens to infect a substantial portion of the planet’s population and perhaps kill millions of people, especially older adults. As billions of dollars flow into research and development efforts aimed at controlling the virus, the pandemic response remains hamstrung by our limited understanding of how to generate effective immunity, particularly in the elderly.
As we age, health conditions associated with aging, particularly noncommunicable diseases such as heart disease, cancers, and metabolic and autoimmune diseases, combined with treatments for these diseases and with immune senescence, substantially affect responses to vaccines and infectious diseases. 1 Angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor for SARS-CoV-2, the virus that causes Covid-19, and it has been suggested that differential levels of ACE2 in the cardiac and pulmonary tissues of younger versus older adults may be at least partially responsible for the spectrum of disease virulence observed among patients with Covid-19. These findings have led to debate regarding the potential use of ACE inhibitors in the context of the pandemic. 2 This idea highlights the need for longitudinal studies in aging populations — such as the Rotterdam Study (a prospective cohort study focused on cardiovascular, neurologic, ophthalmologic, and endocrine diseases) — to examine the impact of coexisting conditions and therapies on the effects of vaccines and infectious diseases.
Even as the brunt of severe illness from Covid-19 is being borne by aging adults, we are navigating partially blind in efforts to develop vaccines and therapies to stop this and future pandemics, since we lack knowledge of the mechanisms of immunity to protect this population. If we can delineate principles of effective immunity in the elderly, we might also be able to develop new strategies for broader disease prevention and control in older populations.
Covid-19 has highlighted the vulnerability of aging populations to emerging diseases. This susceptibility to disease and death is also a major challenge for the development of vaccines and immunotherapeutic agents. Numerous studies have shown that vaccine efficacy decreases significantly with age, a reduction that is thought to be driven by the progressive age-related decline of innate and adaptive immune responses. 3 Yet we know that some older people are protected by generally poorly performing vaccines, and some vaccines work very well in elderly populations: the Shingrix vaccine for shingles, for example, is 90% effective in people over 70. What accounts for the variability in immune responses from one elderly person to another? How can we use our understanding of this variability in developing new and improved vaccines and therapies?
Far from being mere academic exercises, the answers to these questions are critical to the future of global health. The Covid-19 experience in aging populations offers a window into the profound, long-term, global demographic challenges the world is facing. According to the United Nations, projections indicate that by 2050 there will be more than twice as many people over 65 as there are children under 5, and the number of people 65 years of age or older globally will surpass the number of people 15 to 24 years of age. 4
This global aging will create widespread public health challenges, dramatically increasing the burden of noncommunicable diseases and exposing our vulnerability to infectious diseases. The number of deaths related to antimicrobial resistance is projected to reach 10 million per year by 2050, exceeding mortality from cancer. Climate change could put an additional 1 billion people at risk from tropical vectorborne diseases, and potentially pandemic diseases are emerging with greater frequency. Protecting aging populations will be a central, if not the primary, question in maintaining global health and biosecurity.
Recent technological advances in biomedical and computer sciences provide an unprecedented opportunity to decode the human immune system. Innovations in systems biology applied in clinical immunology studies now allow immensely detailed measurements of human transcriptomic, proteomic, immune, and metabolic responses. Such studies have already led to improved understanding of the extent to which human responses within a population vary on several parameters, and of the influence of the microbiome in host immunity, leading to considerations for novel vaccination and immune-therapeutic strategies. 5 For example, many baseline “omic” signatures predictive of vaccine-induced immunity have been associated with innate immune parameters, which suggests that specific and novel immunomodulators may enhance future vaccines and immunotherapies.
Moreover, advances in bioinformatics, causal inference, and artificial intelligence (AI) — building on AI advances from other fields, such as biomedical imaging — enable analyses of large-scale data sets that can help in determining the key elements and principles of effective human immunity. These tools offer the potential for elucidating the mechanisms that differentiate people who have a response to vaccines from those who do not, and for clarifying why some people develop effective immune responses to disease. These answers should provide the basis for accelerating the discovery and development of new vaccines, diagnostics, and therapies for major diseases. Generating systems-biology data on an unprecedented scale should also enable computational scientists to begin to develop AI models of human immunity, which, if successful, could transform product development, enabling computer-generated simulation trials to facilitate faster and cheaper development, with a much greater probability of success.
Innovative new studies are needed to investigate questions of why some people have stronger responses to vaccines or diseases than others so that we can better prevent and treat disease. This undertaking will require a global approach and a radically new vision — one that spans diseases and sectors of society, bringing together academia, industry, government, and philanthropic organizations. Covid-19 is already catalyzing collaboration among these sectors, and this work must continue beyond the pandemic.
Thus, the tools are now available to decipher the principles of effective immunity in aging populations. If investigators study cohorts of elderly people longitudinally and globally and probe their immune systems with licensed vaccines to distinguish people with effective responses from those without, and apply cutting-edge tools from systems biology and AI, it should be feasible to identify biomarkers for effective immunity in this population, which could then be applied to other vulnerable populations, such as those living in low- and middle-income countries. Over the long term, the research agenda will need to include cultivation of a new generation of multidisciplinary scientists trained in biomedical, informatics, and computer sciences in order to fully prepare for the next wave of emerging diseases.
Covid-19 is highly transmissible, causes relatively high mortality, particularly in aging populations, and has emerged globally in our highly interconnected world. Short-term efforts to quickly develop lifesaving vaccines and therapeutics are of the utmost importance.
In the long term, however, we will have to shift from investing primarily in disease-specific research to simultaneously targeting sufficient resources toward decoding the human immune system, particularly for the world’s most vulnerable populations. Such an effort could accelerate the development of new vaccines, diagnostics, and treatments — not just for Covid-19, but also for future emerging pathogens as well as the noncommunicable diseases of aging that are our major global killers. We need bold action as soon as possible to help all of humanity live longer and healthier lives.
The three major types of lymphocyte are T cells, B cells and natural killer (NK) cells.  Lymphocytes can be identified by their large nucleus.
T cells and B cells Edit
T cells (thymus cells) and B cells (bone marrow- or bursa-derived cells [a] ) are the major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity, whereas B cells are primarily responsible for humoral immunity (relating to antibodies). The function of T cells and B cells is to recognize specific "non-self" antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored maximally to eliminate specific pathogens or pathogen-infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens some T cells, called T helper cells, produce cytokines that direct the immune response, while other T cells, called cytotoxic T cells, produce toxic granules that contain powerful enzymes which induce the death of pathogen-infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells. Throughout the lifetime of an animal, these memory cells will "remember" each specific pathogen encountered, and are able to mount a strong and rapid response if the same pathogen is detected again this is known as acquired immunity.
Natural killer cells Edit
NK cells are a part of the innate immune system and play a major role in defending the host from tumors and virally infected cells.  NK cells modulate the functions of other cells, including macrophages and T cells,  and distinguish infected cells and tumors from normal and uninfected cells by recognizing changes of a surface molecule called MHC (major histocompatibility complex) class I. NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells.  They are named "natural killer cells" because they do not require prior activation in order to kill cells which are missing MHC class I.
Dual expresser lymphocyte - X cell Edit
The X lymphocyte is a reported cell type expressing both a B-cell receptor and T-cell receptor and is hypothesized to be implicated in type 1 diabetes.   Its existence as a cell type has been challenged by two studies.   However, the authors of original article pointed to the fact that the two studies have detected X cells by imaging microscopy and FACS as described.  Additional studies are obviously required to determine the nature and properties of X cells (also called dual expressers).
Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow.  This process is called haematopoiesis. All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis. In mammals, B cells mature in the bone marrow, which is at the core of most bones.  In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick,  (B for bursa) and not from bone marrow as commonly believed. T cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they survey for invading pathogens and/or tumor cells.
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells). Memory T cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure they live weeks to several years, which is very long compared to other leukocytes. [ citation needed ]
Microscopically, in a Wright's stained peripheral blood smear, a normal lymphocyte has a large, dark-staining nucleus with little to no eosinophilic cytoplasm. In normal situations, the coarse, dense nucleus of a lymphocyte is approximately the size of a red blood cell (about 7 μm in diameter).  Some lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear zone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be viewed with an electron microscope. The ribosomes are involved in protein synthesis, allowing the generation of large quantities of cytokines and immunoglobulins by these cells.
It is impossible to distinguish between T cells and B cells in a peripheral blood smear.  Normally, flow cytometry testing is used for specific lymphocyte population counts. This can be used to determine the percentage of lymphocytes that contain a particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example, cytokines using intracellular cytokine staining (ICCS)). In order to study the function of a lymphocyte by virtue of the proteins it generates, other scientific techniques like the ELISPOT or secretion assay techniques can be used. 
|Class||Function||Proportion (median, 95% CI)||Phenotypic marker(s)|
|Natural killer cells||Lysis of virally infected cells and tumour cells||7% (2–13%)||CD16 CD56 but not CD3|
|T helper cells||Release cytokines and growth factors that regulate other immune cells||46% (28–59%)||TCRαβ, CD3 and CD4|
|Cytotoxic T cells||Lysis of virally infected cells, tumour cells and allografts||19% (13–32%)||TCRαβ, CD3 and CD8|
|Gamma delta T cells||Immunoregulation and cytotoxicity||5% (2–8%)||TCRγδ and CD3|
|B cells||Secretion of antibodies||23% (18–47%)||MHC class II, CD19 and CD20|
In the circulatory system, they move from lymph node to lymph node.   This contrasts with macrophages, which are rather stationary in the nodes.
A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as the percentage of lymphocytes to the total number of white blood cells counted.
A general increase in the number of lymphocytes is known as lymphocytosis,  whereas a decrease is known as lymphocytopenia.
An increase in lymphocyte concentration is usually a sign of a viral infection (in some rare case, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person).   A high lymphocyte count with a low neutrophil count might be caused by lymphoma. Pertussis toxin (PTx) of Bordetella pertussis, formerly known as lymphocytosis-promoting factor, causes a decrease in the entry of lymphocytes into lymph nodes, which can lead to a condition known as lymphocytosis, with a complete lymphocyte count of over 4000 per μl in adults or over 8000 per μl in children. This is unique in that many bacterial infections illustrate neutrophil-predominance instead.
A low normal to low absolute lymphocyte concentration is associated with increased rates of infection after surgery or trauma. 
One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects and destroys T cells (specifically, the CD4 + subgroup of T lymphocytes, which become helper T cells).  Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect healthy people. The extent of HIV progression is typically determined by measuring the percentage of CD4 + T cells in the patient's blood – HIV ultimately progresses to acquired immune deficiency syndrome (AIDS). The effects of other viruses or lymphocyte disorders can also often be estimated by counting the numbers of lymphocytes present in the blood.
Tumor-infiltrating lymphocytes Edit
In some cancers, such as melanoma and colorectal cancer, lymphocytes can migrate into and attack the tumor. This can sometimes lead to regression of the primary tumor.
Immunosenescence is a multifactorial condition leading to many pathologically significant health problems in the aged population. Some of the age-dependent biological changes that contribute to the onset of immunosenescence are listed below:
- (HSC), which provide the regulated lifelong supply of leukocyte progenitors that are in turn able to differentiate into a diversity of specialised immune cells (including lymphocytes, antigen-presentingdendritic cells, and phagocytes) diminish in their self-renewal capacity. This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity  and the shortening of telomeric terminals of chromosomes.
- There is a notable decline in the total number of phagocytes in aged hosts, coupled with an intrinsic reduction of their bactericidal activity. 
- The cytotoxicity of natural killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age.  The age-associated impairment of dendritic antigen-presenting cells (APCs) has profound implications as this translates into a deficiency in cell-mediated immunity and thus, the inability for effector T-lymphocytes to modulate an adaptive immune response (see below).
- A decline in humoral immunity caused by a reduction in the population of antibody producing B-cells along with a smaller immunoglobulin diversity and affinity. 
As age advances, there is decline in both the production of new naive lymphocytes and the functional competence of memory cell populations. This has been implicated in the increasing frequency and severity of diseases such as cancer, chronic inflammatory disorders, breakthrough infections and autoimmunity.   A problem of infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by underlying chronic conditions.  Ultimately, this provides problems in diagnosis and, subsequently, treatment.
In addition to changes in immune responses, the beneficial effects of inflammation devoted to the neutralisation of dangerous and harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.  It should be further noted that changes in the lymphoid compartment is not solely responsible for the malfunctioning of the immune system in the elderly. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes. 
The functional capacity of T-cells is most influenced by the effects of aging. In fact, age-related alterations are evident in all stages of T-cell development, making them a significant factor in the development of immunosenescence.  After birth, the decline of T-cell function begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation following the migration of precursor cells from the bone marrow. This age-associated decrease of thymic epithelial volume results in a reduction/exhaustion on the number of thymocytes (i.e. pre-mature T-cells), thus reducing output of peripheral naïve T-cells.   Once matured and circulating throughout the peripheral system, T-cells still undergo deleterious age-dependent changes. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, which makes the body more prone to a variety of infectious and non-infectious diseases. 
By age 40, an estimated 50% to 85% of adults have contracted human cytomegalovirus (HCMV), which is believed to be a major cause of immunosenescence,  although this is controversial.  Despite the fact that an average of 10% (and up to 50%) of the CD4 and CD8 memory T cells of HCMV-infected persons may be CMV-specific, these persons do not have a higher fatality rate resulting from other infections. 
Increased numbers of MDSCs are observed in bone marrow, spleen and peripheral blood of aged mice. Such accumulation of MDSCs impairs senescence and results in the diminished ability of tumor cell clearance and changes in homeostasis and energetic metabolism.  Moreover, the increased appearance of MDSCs within a tissue leads to the induction of IL-10 and TGFβ secretion that further promotes tumor cell expansion. 
T-cell components associated with immunosenescence include:
- reduction in the CD4+/CD8+ ratio
- the expression of PD-1 increases 
- impaired development of CD4+ T follicular helper cells, which are specialized in facilitating peripheral B cell maturation, and the generation of antibody-producing plasma cells and memory B cells
- deregulation of intracellular signal transduction capabilities 
- diminished capacity to produce effector lymphokines
- shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity 
- down-regulation of CD28 costimulatory molecules 
- cytotoxic activity of Natural Killer T-cells (NKTs) decreases  due to reduction of the expression of cytotoxicity activating receptors (NKp30, NKp46, etc.) and simultaneously increase in the expression of the inhibitory (KIR, NKG2C, etc.) receptors of NK cells 
- reduction of cytotoxic activity due to impaired expression of associated molecules such as IFN-γ, granzyme B or perforin
- impaired proliferation in response to antigenic stimulation 
- the accumulation and the clonal expansion of memory and effector T-cells 
- hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells
- changes in cytokine profile e.g. increased pro-inflammatory cytokines milieu present in the elderly  is employed as a preferential pathway of energetic metabolism and thus functionally impaired mitochondria produce ROS excessively 
- presence of a T cell-specific biomarkers of senescence (circular RNA100783, micro-RNAs MiR-181a) 
As mentioned above, immunosenescence is a complex and spontaneous process, in which various cell subtypes participate. However, the reduced T cell output resulting from the thymus involution seems to carry the greatest importance.  Therefore, the aging progression can be restricted by restoring of the thymus growth that can be achieved by transplantation of proliferative thymic epithelial cells from young mice to aged or defective thymus.  Clinically important seems to be an antidiabetic drug Metformin that has been proven to moderate aging in preclinical studies,  similarly as an antitumor substance Rapamycin.  Also coenzyme NAD+ has shown to be reduced in various tissues in age-dependent manner, thus NAD+ including supplements may have a protective effects.