Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease

Abstract

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master ‘clock of age’ (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin‐like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age‐related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age‐related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age‐related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age‐related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.

Risk of Major Types of Dementias Following Hospital-Diagnosed Infections and Autoimmune Diseases

“…In the current study, we further build on these observations and find that the dementia–infection link is predominantly seen in the short term, and potentially in a more ill subgroup of dementia cases (NMC cases), and in VaD in the long term. These interpretations may indicate that episodes of infection may be a marker of a declining immune system/immunosenescence [ 21 ] rather than reflecting de novo infection, consistent with the idea that immunosenescence predisposes to dementia development [ 21 ]. The differences between the NMC and MC cases in our study suggest that an association between dementias and infections is particularly relevant for a subgroup of cases who might be predisposed to both clinical infections and dementia development.…”

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia

“…Pulmonary diseases caused by influenza virus, pneumococcus, adenoviruses, and other infectious agents are a major cause of death in the very elderly, and broad-spectrum immune boosting (‘trained immunity’) with Bacille Calmette–Guérin (BCG) has been shown to offer significant protection against respiratory infections in the elderly [ 1 ]. The increased prevalence of infectious diseases in the elderly (and perhaps the aging phenotype itself) has been argued to culminate from age-related decline in stem cell renewal that most centrally affects the immune system [ 2 ]. Indeed, there is growing interest in the potential involvement of microbes in the pathoetiology of dementias including Alzheimer’s disease (AD) as well as in Parkinson’s disease, and perhaps also some cancers and diseases of the heart andvasculature.…”

“…Adding to the plausibility that infections might contribute to dementia, there have been a series of clinical cases in which dementia was found to be directly associated with fungal, bacterial, or viral infections, and in some cases dementia remitted following appropriate antimicrobial intervention (reviewed in [ 14 ]). Moreover, it has been argued that aging per se —the greatest risk factor for all types of dementia—is associated with decline of the immune system (immunosenescence) that predisposes to diverse infectious disorders including those of the central nervous system, as substantiated by increased levels of microbes in brain of elderly individuals [ 2 ].…”

“…In studies on individuals aged 19–74 years, abscess and/or lymphadenopathy was seen in ∼3% of vaccine recipients, that generally resolved upon treatment [ 82, 83 ]. Nevertheless, given suggestions that elderly individuals, particularly those at risk of AD, may have some degree of immune decline [ 2 ], close monitoring of vaccine recipients is warranted.…”

Cognitive Impairment in Multiple Sclerosis

“…If one considers disorders such as AD, familial cases of AD (FAD) affect a much smaller proportion of the population. FAD is an autosomal dominant form of a mutated amyloid precursor protein (APP) gene, and occurs in approximately 200 families worldwide [71,95,[98][99][100][101][102]. FAD occurs most often prior to age 55, and results from variable single-gene mutations on chromosomes 1, 14, and 21 [23,103,104].…”