RAGE has a pivotal role in ageing through inflammaging

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Human longevity

Human longevity has evolved considerably during the last century and increased worldwide. As an example, LEB was 45 years old in France in 1900 and is now around 82 years old2. However, there are important differences between developing and developed countries in this regard. First, a greater percentage of this increase is explained by a diminution of infant mortality rates in developing than in developed countries3,4. In Africa (World Health Organization (WHO) region) there were around 7.4 child deaths (under 5 years old) for 1000 inhabitants in 1990, but this quickly decreased to 2.8 by 2015. By comparison in Europe (WHO region), a wealthier region, this ratio was 0.46 in 1990 and 0.12 in 2015 (Fig. 1). This evolution is similar when considering the number of births instead of total population5,6 As a consequence, as child mortality has been very low in rich regions for decades, its evolution (if it exists) has proportionally significantly less influence on overall LEB compared to that of developing regions.

Longevity in other species

Longevity in other species has been described and varies immensely, ranging from a few hours to thousands of years. The study of lifespan in many species has shown that there are links between fertility, the size of progeny and longevity. It has also been shown that when lifespan increases, fertility decreases and vice-versa27–29. Strikingly, data from 133 mammal species, gathered from the animal ageing and longevity database (AnAge)30,31, show that there is a clear correlation in mammals between gestation time and their longevity (r² = 0.5401, p < 0.0001) (Fig. 4a). Balaena mysticetus, the longest-lived mammal with an estimated age of 211 years (± 35 years) for the oldest specimen32,33, is a clear outlier in this regard and its extreme longevity | Ageing | Demography of ageing might be explained by factors that are specific to this species. Similarly, the longevity of Homo sapiens, reported to be the second longest-lived mammal, is also higher than anticipated by this correlation and can again be mostly explained by the specific living conditions that allow greater longevity than in other species. While we can therefore predict the longevity of a species in general terms, it is probably not possible to determine the longevity of an individual as intra- and inter-species variations in longevity or lifespan are probably governed by different mechanisms. In addition, while correlation of longevity and average adult weight of a species is very strong in the heaviest mammals, there is a large variation in smaller ones (Fig. 4b). Thus, longevity is not simply bound to the complexity of an organism but is also linked to its reproductive capabilities.

The evolution of ageing

Current research has not shown genes dedicated to ageing. As discussed below, every current deletion of genes that have an impact on lifespan always involve drawbacks. Hence, there is no known program of ageing, i.e. a genetic program designed to limit a species’ lifespan. The tremendous difference in longevity between species suggests, however, that there are some “programs of longevity”, i.e. genes that have evolved to meet requirements that ensure the sustainability of a species. Complex organisms that require long gestation or egg incubation times need correspondingly longer lifespans that correspond to their reproduction capabilities. On the other hand, species that have higher reproduction capacities have a shorter lifespan – but it does not mean that they have evolved mechanisms that restrict their lifespan. Rather, in accordance with the law of parsimony, it is more sensible to think that mechanisms that extended lifespan could not have been conserved because they would have caused local overpopulation and thereby limited nutrient accessibility. Thus, it would not be viable to select modifications that increase longevity in highly proliferative organisms, and shorter lifespan in such organisms is the result of an absence of selection for modifications that increase it since there is no evolutionary benefit and hence no selection pressure. This hypothesis is simpler and requires less assumptions than a hypothesis suggesting selection of mechanisms that limit lifespan.

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The antagonistic pleiotropy hypothesis

The antagonistic pleiotropy hypothesis is one of the main hypotheses in the biology of ageing purporting to explain the existence of lifespan-limiting genes. This hypothesis notably suggests that evolution selects some genes of which expression is very beneficial early in life at the cost of a more negative impact in later life. Their selection during evolution would be allowable owing to their beneficial effects on survival and reproduction being expressed during a crucial period of natural selection70. Thus, several genes have been identified as important during development but which become deleterious in adults, often possessing pro-ageing properties in later life.
The insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) is involved in cell survival and proliferation and in protein synthesis, is highly conserved through evolution, and is indubitably the best representative of obvious antagonistic pleiotropy (Fig. 6a). Knock-out or knock-down of members of this pathway always leads to a consequent alteration of longevity and is always associated with developmental consequences. In Caenorhabditis elegans, knock-out of daf-2, the ortholog of the human IGF-1 receptor (IGFR-1R), doubles or triples median and maximal lifespan71,72 but with a concurrent ~20% reduction in fertility73. Although reduction in fertility is quite low, daf-2 mutants are nonetheless quickly outcompeted by control worms, suggesting an overall reduced fitness73. Although lifespan increase is smaller, identical results are found in hypomorphic mutations of age-174,75. Similar results, but to different extents, have been reported in S. cerevisiae, D. melanogaster and M. musculus76–79. Interestingly, the growth hormone (GH), produced by the pituitary in mice, controls IGF-1 secretion. Alteration of the pituitary development, such as in the Ames and Snell dwarf mice, significantly increases lifespan while growth and fertility are greatly reduced80–82. In humans, people with homozygous mutations or deletion on the GH receptor gene exhibit the Laron syndrome. They present multiple deficiencies in development leading to dwarfism but are notably well-protected against pathologies such as cancer and diabetes83,84. However, no increase in life expectancy has so far been reported in these people.

Table of contents :

List of figures
List of tables
List of abbreviations
1 | Ageing
1.1 | Definition
1.2 | Demography of ageing
1.2.1 | Human longevity
1.2.2 | Longevity in other species
1.3 | Mechanisms of ageing
1.3.1 | The evolution of ageing
1.3.2 | The antagonistic pleiotropy hypothesis
1.3.3 | The hallmarks of ageing
1.4.1 | Physiological systems age-related decline
1.4.2 | Kidney physiological ageing
1.4.3 | Age-related disorders
1.5 | Interventions that have an impact on lifespan and healthspan
1.5.1 | Modulation of cells
1.5.2 | Genetic models
1.5.3 | Pharmacologic interventions
1.5.4 | Behaviour modulation
2 | Glycation and advanced glycation end-products
2.1 | Definition and formation
2.2 | Advanced glycation end-products
2.2.1 | The structures of AGEs
2.2.2 | Carboxymethyllysine
2.3 | Deleterious effects of AGEs
2.4 | AGEs during ageing
2.5 | AGEs and age-related diseases
3 | The Receptor for Advanced Glycation End-products
3.1 | The receptors for AGEs
3.2 | RAGE structure
3.3 | RAGE expression
3.4 | RAGE ligands
3.4.1 | Advanced glycation end-products
3.4.2 | HMGB1
3.4.3 | Calgranulins
3.4.4 | Amyloid fibrils
3.4.5 | Complement components
3.4.6 | Other RAGE ligands
3.5 | RAGE and its inflammatory signalling
3.6 | Physiological role of RAGE
3.7 | RAGE-associated pathologies
3.7.1 | Non age-related diseases
3.7.2 | Age-related diseases
1 | Instrumental role of RAGE in ageing
2 | Unpublished results
2.1 | Introduction
2.2 | Methods
2.2.1 | Animal experimentation
2.2.3 | Biologic parameters
2.2.4 | Histological analyses
2.2.5 | Western Blot
2.2.6 | RT-qPCR
2.2.7 | Mesangial cells isolation
2.2.8 | Immunocytofluorescence
2.2.9 | Statistical analysis
2.3 | Complementary results
2.4 | Isolation and characterisation of mesangial cells
1 | Summary of the results
2 | Discussion
2.1 | Effects of dietary CML are outcompeted at old age
2.2 | ApoA-II amyloidosis is a relevant marker and cause of ageing
2.3 | Metabolism is partially altered by RAGE
2.4 | RAGE induced-oxidation is arguably determinant in ageing
2.5 | RAGE has a pivotal role in ageing through inflammaging
2.6 | RAGE signalling potentially accelerates sarcopenia
2.7 | RAGE physiological role remains imperceptible and might be compensable
3 | Future directions


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