Periodic Reporting for period 1 - ComBATageing (Exploiting superlongevous model mammals to explore new links between protein and organelle homeostasis and lifespan extension)
Periodo di rendicontazione: 2021-09-01 al 2023-08-31
Over the past decades, humankind has witnessed a rapid and profound change in our lifestyles as a direct or indirect consequence of the unparalleled number of technological and scientific achievements characterising the modern era. This global-scale technological revolution has interested every aspect of our lives, leading to the birth of new social and cultural archetypes as far as determining changes in our environment and affecting our biology. One of the most notable effects of this swift step forward in technology, and more precisely of the advances in medical sciences and achievement of healthier lifestyles, can be observed in the exponential increase in population and average longevity records worldwide. It has been predicted that a baby born today would be able to live up to 142 years of age. The striking increase in predicted lifespan coupled with this exceptional demographic growth will drastically affect the structure of forthcoming human populations, leading to a gradual yet unavoidable change in its structure and age composition. The number of people over 60 years of age will drastically increase (~3 times) at the expense of the younger age cohorts. Future human population will thus be bigger in size and older globally.
Age-related illnesses represent today the first cause of death and the most debilitating pathologies for humans .These include cancer, cardiovascular diseases, neurodegenerative disorders (dementia, Parkinson’s, Alzheimer’s, Huntington’s diseases) together with arthritis, decreased mobility, hearing and sight loss, etc. Despite an intensifying scientific effort in fighting back the deleterious effects of ageing, the rate of incidence of age-related illnesses remains high today and, in the predicted scenario of a bigger and older human population, is intended to grow. Despite being one of the most important risk factors for our welfare, today we are still distant from a full understanding of complex functioning of the ageing process.
Nature, provides several examples of species which naturally evolved exceptional longevity. These organisms may be optimal candidates for unveiling the role of various molecular compounds in modulating the pace of ageing and the destructiveness of age-related illnesses.
Within mammals a correlation exists between body-size and longevity, with bigger species living longer than small taxa. Bats can live more than 40 years despite the relatively small size (5 - 20 grams) and high metabolic rates. This translates in being able to live 9 - 10 times more than expected given their body-size. Moreover, bats do not show almost any change in their ageing phenotype, with young individual being undistinguishable, at least macroscopically, from geriatric ones, and a remarkably low incidence of age-related illnesses, including cancer. These features make bats the “longevity specialists” among mammals.
During my past research I focused on the study of age-related loss of mitochondrial and protein homeostasis efficiency in bats. This choice followed the assumption that, as they are the only mammals capable of performing active flight, they may have evolved a more efficient system for coping with an enhanced intracellular exposure to metabolic stress. This work has been designed to characterise and isolate specific adaptations of protein quality control and organellar turnover systems in bats through a comparative approach with other models such as mice and humans. Once isolated, the molecular targets will be pharmacologically and genetically manipulated to assess their role and relevance in determining cellular survival and ageing. Finally, a phylogenomic analysis will be carried out to determine the presence of any trace of adaptive selection occurring in autophagy- and proteasome-related genes in bats. The integrative nature of this work will provide a first encompassing analysis of cellular homeostasis maintenance and ageing in a new, revolutionary long-lived mammalian model, potentially providing novel molecular targets for transational application against age-related diseases.
Age-related illnesses represent today the first cause of death and the most debilitating pathologies for humans .These include cancer, cardiovascular diseases, neurodegenerative disorders (dementia, Parkinson’s, Alzheimer’s, Huntington’s diseases) together with arthritis, decreased mobility, hearing and sight loss, etc. Despite an intensifying scientific effort in fighting back the deleterious effects of ageing, the rate of incidence of age-related illnesses remains high today and, in the predicted scenario of a bigger and older human population, is intended to grow. Despite being one of the most important risk factors for our welfare, today we are still distant from a full understanding of complex functioning of the ageing process.
Nature, provides several examples of species which naturally evolved exceptional longevity. These organisms may be optimal candidates for unveiling the role of various molecular compounds in modulating the pace of ageing and the destructiveness of age-related illnesses.
Within mammals a correlation exists between body-size and longevity, with bigger species living longer than small taxa. Bats can live more than 40 years despite the relatively small size (5 - 20 grams) and high metabolic rates. This translates in being able to live 9 - 10 times more than expected given their body-size. Moreover, bats do not show almost any change in their ageing phenotype, with young individual being undistinguishable, at least macroscopically, from geriatric ones, and a remarkably low incidence of age-related illnesses, including cancer. These features make bats the “longevity specialists” among mammals.
During my past research I focused on the study of age-related loss of mitochondrial and protein homeostasis efficiency in bats. This choice followed the assumption that, as they are the only mammals capable of performing active flight, they may have evolved a more efficient system for coping with an enhanced intracellular exposure to metabolic stress. This work has been designed to characterise and isolate specific adaptations of protein quality control and organellar turnover systems in bats through a comparative approach with other models such as mice and humans. Once isolated, the molecular targets will be pharmacologically and genetically manipulated to assess their role and relevance in determining cellular survival and ageing. Finally, a phylogenomic analysis will be carried out to determine the presence of any trace of adaptive selection occurring in autophagy- and proteasome-related genes in bats. The integrative nature of this work will provide a first encompassing analysis of cellular homeostasis maintenance and ageing in a new, revolutionary long-lived mammalian model, potentially providing novel molecular targets for transational application against age-related diseases.
During the past 2 years, biological samples were collected from 300+ wild bats to generate cellular models suitable for in vitro studies. Primary fibroblasts cells were derived and cultured after a protocol optimization phase, allowing the set-up of a research facility specialised in the study of these alternative biological models. A first characterisation of bat cells was then performed by integrating several different methodologies including electron microscopy, immunoblotting, proliferation assays and cellular homeostatic reporters (DNA-damage, autophagic/proteasomal activity). Following this, multi -omics analyses were performed trough a comparative approach with samples derived from mice and human counterparts. Finally, a phylogenomic analysis on the whole mammalian clade was carried out to detect traces of adaptive evolution in the bats’ genome. Overall, the study allowed to detect some unique features of bat cellular dynamics (near absence of proliferative senescence activation, enhanced growing abilities) and some unique features in the bioenergetic, proteostatic and anti-tumoral functions. Novel data were gathered for the first time, answering some open questions in the peculiar evolutive process of this taxon of mammals. Moreover, 25 genes were identified thanks to the phylogenomic analysis to be under selection in bats versus the rest of the mammalian clade, thus providing new molecular targets for future translational studies on age-related topics. All these data represent a first ever integrative profiling approach to describe some of the molecular adaptations arguably responsible of bats’ exceptional longevity. Generating such results allowed to attract interest at international conferences on aging and set up collaborations with researchers working with unconventional mammalian study models . This allowed to set up new studies focusing on the integrative analysis of the bioenergetic and immune systems with the degradative function of autophagy, in light of the results generated during the MCSA funded project.
The use of non-conventional biological models such as bats for transaltional studies is still at an early stage among the scientific community, nevertheless this work allowed to obtain novel data on bat proliferative patterns and bioenergetic plasticity, novel molecular targets for translational application and a first integrated investigation of evolutive adaptations in bats versus the rest of the mammalian clade which may have contributed to the evolution of longevity of these animals.
The work also confirmed some assumption which were only theoretically hypothesized for long-lived mammalian biological models on the evolution of longevity and cancer tolerance, thus contributing to the advance in the state of the art on molecular evolution research.
All the data generated in this work will represent the basis for future studies on decihpering the molecular adaptations responable of bats' halted aging process, with potenyially huge implications in public health economy and society.
The work also confirmed some assumption which were only theoretically hypothesized for long-lived mammalian biological models on the evolution of longevity and cancer tolerance, thus contributing to the advance in the state of the art on molecular evolution research.
All the data generated in this work will represent the basis for future studies on decihpering the molecular adaptations responable of bats' halted aging process, with potenyially huge implications in public health economy and society.