Searching for primary literature sources reporting on the relationship between the effects of different factors (i.e. age, sex, ethnicity, endogenous and exogenous compounds) on the levels of serum IgA, IgG and IgM in all human age groups has been carried out in google, PubMed and google scholar with a range of planned search terms related to the topic of this review which is listed as follow:

Levels of serum immunoglobulins in human

Determinants of serum immunoglobulin levels

Reference ranges of serum immunoglobulins in humans

Immunoglobulin synthesis mechanism

Genome function

Major types of genes

Ageing

Biological Changes associated with Ageing

Only original and review articles were retrieved. 41 full text articles which were available online were downloaded and saved on a computer for possible inclusion in the study. The title and abstract of 8 other research articles which were not open access were also considered for possible inclusion in the report of this systematic review.

First, judgment on the quality of primary study results retrieved from different databases has been made based on the methodological quality, content and subject relevance for inclusion. The results of studies that are associated with specific health conditions as determinant factors of the levels of serum immunoglobulins were excluded. Some other studies that had conflicting results with the topic of this review article were also excluded. The results of primary studies relevant to the topic of this systematic review have been identified and appraised for their suitability for inclusion.

Of the 49 different literature sources retrieved from different databases, a total of 42 review and research articles that have satisfied the eligibility criteria mentioned above have been considered for data extraction. There was, however, a challenge to find a research or review article with a full report on the levels of serum immunoglobulins in all age groups. Therefore, the levels of immunoglobulins in the blood serum of different age groups have been extracted from different studies with similar methodological quality, content and subject relevance and combined in the report of this review article. Only research and review articles that had reported the different factors (age, sex, ethnicity, lifestyle practices, and xenobiotics) associated with the levels of serum immunoglobulins in human and animal studies have been selected and filed to be included in the report of this systematic review article.

First, the effects of different xenobiotics at different amounts on the levels of serum Igs have been extracted from different animal studies. And then, the effects of age, sex and ethnicity and lifestyle practices on the levels of serum immunoglobulins in different age groups have been extracted from the results of different population-based cohort studies. Judgment on the magnitude of other biological changes such as loss of muscle tissue, loss of bone density and joint flexibility associated with ageing has also been made. Finally, the relationships between the effects of xenobiotics and ageing have been assessed, arranged, processed and analysed using a computer package (Microsoft office word and excel 2013). The subjects that this study dealt with have been identified and organized into meaningful sections and subsections. For completeness, data from different data sources were used for the compilation of this review report.

Validated data from different literature sources were presented in form of tables, pictures and use of descriptive statements under the themes mentioned in the result and discussion sections of this systematic review.

The results of most studies have demonstrated that the trajectory of the Igs immune response against the different levels of doses of xenobiotics was highly associated with the trajectory of biological changes associated with ageing in humans (Figure 1)(Figure 2) 4571314151617181920212223. The efficiency of immunoglobulins immune response was inversely related to the amount of harmful molecules of test compounds administered into the body systems 5 which was evaluated against the levels of Igs in the blood serum of Balb c mice treated with different amounts of doses orally. The response efficiency of IgM immune response was high against the lower amounts of test compounds and low against the higher amounts of the same test compounds administered to study animals in the same route (Table 1, Figure 1) 5.

The relationship between alcohol consumption and concentration of serum Igs was also described in the reports of different studies on humans 789101112. In the report of these studies, there was a lower level of IgG in the blood serum of moderate alcohol consumers compared to non-consumers 8. The research results for IgM demonstrated that there was lower serum concentrations with higher alcohol consumption 9 and higher with moderate beer consumption 912. A positive relation was, however, reported between alcohol consumption and the levels of IgA in blood serum 7.

The association of hormones, either endogenous or exogenous (predominantly contraceptives or corticosteroids), with the levels of serum immunoglobulins was assessed by Samer R. Khan et al 7. The association of contraceptives with serum Igs levels was heterogeneous. Oral corticosteroids were associated with lower IgG levels and a longer duration of treatment led to a slower recovery in the concentration of serum IgG afterward 7. The report indicated that the prostaglandin EI analogue misoprostol did not change serum immunoglobulins level 7.

The association of a dietary factor with serum levels of immunoglobulins was also assessed by Samer R. Khan et al using 23 study reports. The majority reported on the supplementations of micro/macronutrients or probiotics and few of them on the nutritional status or fasting in relation to the level of serum immunoglobulins 7. Most dietary components were not associated with serum immunoglobulins level. Consumption of Laycium Barbarum juice, resistant corn starch, or saffron tablets, however, was associated with higher IgG levels. Saffron supplementation and roots of North American ginseng were associated with lower IgM and IgA levels respectively. Three observational studies assessed the correlation between dietary components and serum immunoglobulins level and established a positive correlation between dietary energy and carbohydrates with IgA and a negative correlation between 25-hydroxyvitamin D levels and IgA 7.

The association of smoking with the levels of serum immunoglobulins has been reported in different studies. A study conducted by Yang M et al has reported that there were lower levels of IgM in cigarette smoking individuals compared to non-smokers 9. Twelve studies assessed by Samer R Khan et al reported that there were lower IgA and IgG levels in the blood serum of cigarette smokers compared to non-smokers or compared to ex-smokers regardless of daily cigarettes smoked and duration of smoking 7. The study reported that there were also lower IgM levels in the blood serum of smokers compared to non-smokers 7.

Ageing refers to the overall processes of biological changes in the lifespan of animals and humans in which its mechanism is not yet well known. It causes innumerable biological changes within the different biological systems of the body during its transition period from infancy to late adulthood stage (old age) 18. The biological changes during the transition from the infancy to adulthood stage normally exhibit transformational changes during which a person has gradually reached the highest attainable maturation level both physically and mentally. It is naturally characterised by a progressive improvement in the biological functions of the body systems. Ageing causes both positive and negative impacts on the function of the body systems at different stages. For example, the efficiency of the immune system is normally reaching its highest quality during the process of biological changes to the adulthood stage while it is getting to its lowest quality during the process of biological changes to late adulthood stage (old age). For example, in the first year of human life, the level of immunoglobulins is increasing quickly perhaps because of antigenic challenges from the environment (Figure 4). By one year of age, the concentration of IgG, IgM and IgA in blood serum is approximately 60%, 100% and 30% respectively, of the concentrations in adult blood serum (Figure 4) 1828. However, the results of most research demonstrated that there is a decline in the level of serum immunoglobulins mainly IgM with increased age which may contribute to the increased susceptibility of elderly individuals to infectious diseases (figure 2 and Figure 4) 471314151617. For example, most of the research and review articles assessed in this systematic review have shown that the decline of serum IgM levels was associated with ageing 4678910111213141516171819202122232425262728293031. The level of serum concentration of IgM in younger age groups was higher than older age groups (Figure 2 and Figure 4). According to the reports of different studies, there was also a trend for lower IgG levels associated with ageing (Figure 4) 471314151617. Furthermore, the biological changes in other biological systems are also associated with ageing. The skeletal system which was structured with less bone density at the infancy stage would become structured with high bone density, the muscular system which was less toned at the infancy stage would become highly firm and strong, and the joints exhibit conscious movement with less duration of motion and flexibility as compared to the late adulthood stages (old age) (Figure 3) 2122. It also brings an improvement in cognition and emotion in which a person becomes able to solidify his/her abstract thinking and start to understand cause and effect 23. This means that a person becomes able to think hypothetically and able to make decisions independently, plan for the future, and assume adult responsibilities, follow rules and regulations to maintain the systems and institutions that are already in place 23. However, all these biological advancements acquired during the early adulthood stages would be reversed during the biological changes in old age 2425262728. For example, cognitive, visual and memory impairment among many others are the undesirable biological changes associated with the biological transitions in the late adulthood stage. The muscular system becomes less toned and the duration of joint movement is increasing with less degree of flexibility. The social characteristics of a person become a type of an infancy stage in which it depends on caregivers for its need 23. Thus, the ageing process encompasses the biological changes that are progressively advancing during the early adulthood stages (approximately < 40 years) followed by biological regressions that are gradually declining during the late adulthood stages (approximately ≥ 40 years) of human life (Figure 3).

In this study, the relationship between the immunoglobulins immune response against graded xenobiotics and the biological changes associated with ageing has been systematically assessed using the reports of different research results on humans and study animals. First, the effects of different xenobiotics at different amounts on the levels of serum immunoglobulins have been studied on Balb c mice which were treated orally 5. Then, the effects of age, sex and lifestyle-based practices on the levels of serum immunoglobulins (IgG, IgA and IgM) in different age groups of humans have been studied using a systematic review of the results of different population-based studies 4678910111213141516171819202122232425262728293031. Finally, the correlations between the different study findings have been assessed and judgment on the possible cause of ageing has been made.

The results of several studies have demonstrated that the undesirable side effects of test compounds have been manifested within a short period of time when the higher doses were administered to Balb c mice in the oral route. It also remained after a long period of time when the lower doses were administered in the same route 536. Study animals treated with different amounts of xenobiotics had no equal opportunity to exist in life but equal fate for death at different lifespans depending on the levels of doses administered into the body (Figure 5). Death was extremely likely following the decline of IgM levels in the blood serum of treated Balb c mice 5. The results of other research assessed in this study have also shown that the levels of serum Igs mainly IgM were inversely related to the amounts of xenobiotics consumed by different study groups 4579. The levels of serum IgM were quickly depleted when the higher doses of test compounds were administered and were quickly increased when the lower amounts of the same test compounds were administered to Balb c mice (Table 1) 5. The levels of serum IgM, IgG and IgA were reported in other population-based cohort studies in which the amounts of Igs, mainly IgM in the blood serum of an individual was also inversely related to the amount of alcohol consumption 479. It should be noted that the synthesis of immunoglobulin molecules is always directed by the genomic DNA through mRNA coding within B lymphocytes which are the major plasma cells responsible for the production of circulating, humoral antibodies which of course are also known as immunoglobulins 237. First, the harmful molecules of xenobiotics bind with a receptor on the surface of B cells which is believed to be immunoglobulin beta and immunoglobulin alpha types that transduce the biological signal into the nucleus of B cells 237. Following the transduction of biological signals, the gene provides the B cells with information to make an immunoglobulin molecule 237. Thus, the signal generated as a result of interaction with the harmful molecules or pathogenic microbes causes the growth and proliferation of B cells and the production of immunoglobulins inside the plasma cells 2. However, several study findings on humans and animals have indicated that the signaling efficiency of Igs has been limited by the higher levels of doses of administered xenobiotics which resulted in low levels of serum Igs which is known as desensitization The response efficiency of a receptor (the relationship between the magnitude of a biological signal elicited and a biological or physiological output) is determined by the efficiency of the feedback response of an effector. The response efficiency of a receptor is being evaluated against the output of a biological system generated as a result of the effector’s feedback mechanism such as the levels of serum immunoglobulins after dosing. A receptor could be part of a molecule, a cell or an organ system in the body which is able to respond to external stimulus and transmit biological signal to an effector. It forms the most important interface between an effector and its environment. An effector, on the other hand, is part of the body which could be a molecule, a cell or an organ system that produces a biological or physiological effect in response to a biological signal from a receptor site. There are different types of intermediate messengers that carry a biological signal from the receptor to the effector site to facilitate the manifestation of such a biological or physiological effect. This means that a biological message from a receptor has no biological or physiological effect without an effector’s feedback response. An organism could no longer exist as a living creature when the biological equilibrium between the efficiency of the receptors and effectors signaling mechanisms is impaired that subsequently leading to a coma in which an effector could no longer respond to the receptors’ message. The existence of life would be ceased soon after the cessation of the effectors’ signaling cascades. Hence, death refers to an organism that has lost complete biological interaction with its environment due to impaired signalling mechanism from the effectors’ site. Thus, the efficiency of the feedback mechanisms of an effector to the receptors’ biological message determines the sustainability of the biological processes of the body systems. However, the sustainability of the different biological and physiological functions has been influenced by the excessive biological signals generated from the receptor types. For example, the signaling efficiency of immunoglobulins has faded away as the amount of doses of xenobiotics administered to study animals has been uniformly increased which resulted in low levels of serum Igs and subsequently caused death (Table 1) 5. Furthermore, the signaling efficiency of our sensory receptors to tastes would usually fade away as the molecules of a substance interacting with the taste buds increases. The signaling efficiency of our sensory receptors to pain would also usually fade away as the amount of alcohol consumption increases and many more to mention. These biological and physiological phenomena are just because the biological equilibrium between the signaling cascades of a receptor and an effector is no longer exists when the amount of a molecule interacting with a receptor type exceeds the response efficiency of an effector. This implies the fact that an effector has a predetermined biological capacity to sustain the natural processes of a biological system. This could be the possible evidence to say that life, in general, has predetermined response efficiency to xenobiotics which determines the efficiency of biological processes to sustain the different functions of the body systems for a limited period of time. This should be because the genome (effector), should have predetermined genetic information encoded in it which determines the transcription efficiency (capacity to process biological molecules) to regulate the different components of the body systems, in this case, the immune system to produce needed biological responses against the undesirable effect of higher doses. Following the depletion of serum Igs levels, study animals started dying at different lifespans depending on the amount of doses administered (Figure 4) 536. This could be possible evidence for the limited transcription efficiency of the genome which was associated with depleted levels of serum Igs during the biological processes of Balb c mice treated with different amounts of doses (Table 1). The limited transcription efficiency of the genome might be the reason why we don’t continue growing throughout our lifespan. Different biological systems ceased viability at some stage in the ageing process of humans and animals. Plants, animals and humans ceased growth at some stage in their lifespan, a woman or an animal ceased ovulation at some stage in their lifespan. There are innumerable other biological losses in the ageing processes of humans and animals which might be associated with the limited transcription efficiency of the genome that determines the viability of the different body systems to produce needed biological molecules such as proteins, fats and carbohydrates to meet the demand of the body. As we age, the biological demand of our body increases in which the limited transcription efficiency of the genome could no longer satisfy the biological processes which ultimately result in pathological and physiological changes such as loss of muscle tissue, loss of vision and hearing, loss of sensation, osteoporosis, reduced bone density and joint flexibility among others 203839404142. This means that the transcription efficiency of the genome (the effector) to instruct the different body systems to maintain their viability would be exhausted at some stage in the lifespan of humans and animals depending on the intensity of its response to the biological signals (receptors’ message). Every one of us could have a minimum or maximum lifespan depending upon our lifestyle-based experiences which could potentially accelerate the ageing processes at different rates.

The viability of our genes determines the efficiency of our biological processes that make the differences who we are, how we respond and survive and what our features look like. For example, different studies by Samer R Khan et al, have described the effects of ethnicity and sex on the levels of different serum immunoglobulins. There were higher levels of serum immunoglobulins in Africans, Asians, Amazonians and Melanesians compared to Caucasians 7. An Afghan study has also reported immunoglobulins level which was higher in the Hazaras compared to other tribes 5. The same study reported that there were higher levels of IgA and IgG, but lower levels of IgM in the blood serum of men compared to women 47. These differences in the amount of serum immunoglobulins are most likely associated with the differences in the genetic information encoded in different genes found in different sex and ethnic groups mentioned above that guide the body systems to produce biological molecules.

Almost every cell in our body contains a complete copy of the genome which contains instructions that guide our cells to make biological molecules such as immunoglobulins, fats and carbohydrates which perform different functions in our biological systems 3233. Each gene carries instructions that determine our features, such as eye and hair colors, and height in which there are different versions of genes for each feature of the body 34. A study conducted by Woodwark C. et al reported that a vast amount of gene types and genetic variations exist that are perhaps divided into five major types in a comprehensive way.

Complementary genes

Supplementary genes

Duplicate genes

Polymeric genes

Sex-linked genes

Due to the increased accuracy of breakpoint mapping of copy number variable region (CNV), it is now possible to classify a gene as Type I, Type III, and Type II” CNV depending upon whether a gene falls entirely within a CNV, overlaps the CNV or actually contains the CNV respectively 34. Type I genes tend to be involved in immune response or sensory receptors while type III genes are involved in cell to cell signaling and type II genes are a complex mix of all three types 32333435.

The findings of different research cited in this systematic review have clearly shown that the biological changes associated with the consumption of different xenobiotics at different amounts were highly related to the biological changes associated with ageing in humans. These research findings might be the possible evidence to say that ageing is caused by the foodstuffs and non-foodstuffs we usually consume, the lifestyles we usually experience and the way of life we usually live in the environment which is potentially accelerating our biological processes by consuming the available biological resources such as the genetic information and the energy that lead to a gradual loss of the viability of biological systems. For example, if we don’t eat, we don’t get old but we die. If we eat frequently, we get old. If we get old, we eventually die. Death is unavoidable in one way or another. Metabolism is, therefore, life-sustaining biological mechanism for a limited period of time by which xenobiotics are bio-transformed into different biological molecules such as immunoglobulins, fats and other biomolecules depending on the transcription factors of a gene that are depleting as we are ageing. Our body has limited available resources to process and transform xenobiotics into biologically needed molecules in which misusing them may defile the natural ageing processes. Sleep is an essential biological cycle that switches off the active state of the body and the mind to restore the lost biological resources during active metabolism. Our lifespan would have been completed within a week if we don’t have a sleep for a few hours every day.

The dose of xenobiotics beyond the biological efficiency of the body, (the capacity of the body systems to process them into needed biological products or harmless metabolites), could undoubtedly cause unhealthy ageing. In other words, the natural processes of life could not continue as usual with the biological activity that does not limited to its biological need. This means that the dose of a substance doesn’t determine biological safety but a biological condition that fulfils the biological need of the body which actually determines a lifespan.