Sub-cellular Biochemistry

The ageing process is highly complex involving multiple processes operating at different biological levels. Systems Biology presents an approach using integrative computational and laboratory study that allows us to address such complexity. The approach relies on the computational analysis of knowledge and data to generate predictive models that may be validated with further laboratory experimentation. Our understanding of ageing is such that translational opportunities are within reach and systems biology offers a means to ensure that optimal decisions are made...

Serotonin or 5-hydroxytryptamine (5-HT) is an important neurotransmitter in the central nervous system and the periphery. Most 5-HT (~99%) is found in the periphery where it regulates the function of the gastrointestinal (GI) tract and is an important regulator of platelet aggregation. However, the remaining 1% that is found in the central nervous system (CNS) can regulate a range of physiological processes such as learning and memory formation, mood, food intake, sleep, temperature and pain perception. More recent work on the CNS of invertebrate model systems has shown that 5-HT can directly regulate lifespan...

In 1999, in a review by Beardsley, the potential of adult stem cells, in repair and regeneration was heralded (Beardsley Sci Am 281:30-31, 1999). Since then, the field of regenerative medicine has grown exponentially, with the capability of restoring or regenerating the function of damaged, diseased or aged human tissues being an underpinning motivation. If successful, stem cell therapies offer the potential to treat, for example degenerative diseases. In the subsequent 20 years, extensive progress has been made in the arena of adult stem cells (for a recent review see (Zakrzewski et al...

Higher access to medical care, advanced diagnostic tools, and overall public health improvements have favored increased humans lifespan. With a growing proportion of older adults, the associated costs to care for ageing-associated conditions will continue to grow. This chapter highlights recent cellular and clinical evidence of platelets at an older age, from the hyperreactive phenotype associated with thrombosis to the well-known hallmarks of ageing identifiable in platelets and their potential functional implications on platelets at an older age...

The World Health Organization estimates that the world's population over 60 years of age will nearly double in the next 30 years. This change imposes increasing demands on health and social services with increased disease burden in older people, hereafter defined as people aged 60 years or more. An older population will have a greater incidence of cardiovascular disease partly due to higher levels of blood fibrinogen, increased levels of some coagulation factors, and increased platelet activity...

Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies...

Circular RNAs (circRNAs) are closed-loop RNA transcripts formed by a noncanonical back splicing mechanism. circRNAs are expressed in various tissues and cell types in a temporospatially regulated manner and have diverse molecular functions including their ability to act as miRNA sponges, transcriptional and splicing regulators, protein traps, and even templates for polypeptide synthesis. Emerging evidence suggests that circRNAs are themselves dynamically regulated throughout development in various organisms, with a substantial accumulation during ageing...

The progression of age triggers a vast number of diseases including cardiovascular, cancer, and neurodegenerative disorders. Regardless of our plentiful knowledge about age-related diseases, little is understood about molecular pathways that associate the ageing process with various diseases. Several cellular events like senescence, telomere dysfunction, alterations in protein processing, and regulation of gene expression are common between ageing and associated diseases. Accumulating information on the role of microRNAs (miRNAs) suggests targeting miRNAs can aid our understanding of the interplay between ageing and associated diseases...

Cellular senescence is a permanent state of growth arrest coupled with profound changes in phenotype that can be triggered by multiple extrinsic or intrinsic stimuli. Senescence is a process-level example of the evolution of ageing mechanisms through antagonistic pleiotropy and plays a primary role in tumour suppression, although evidence is mounting for its involvement in other fundamental physiological processes. Evidence from human premature ageing diseases and from transgenic mice in which it is possible to specifically delete senescent cells is consistent with a model in which the accumulation of senescent cells through the life course is responsible for later life chronic disease and impairment...

Cellular senescence has become a subject of great interest within the ageing research field over the last 60 years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone...

Gap junctions, comprising connexin proteins, create conduits directly coupling the cytoplasms of adjacent cells. Expressed in essentially all tissues, dynamic gap junction structures enable the exchange of small molecules including ions and second messengers, and are central to maintenance of homeostasis and synchronized excitability. With such diverse and critical roles throughout the body, it is unsurprising that alterations to gap junction and/or connexin expression and function underlie a broad array of age-related pathologies...

The proteasome is a multi-subunit proteolytic complex that functions to degrade normal proteins for physiological regulation and to eliminate abnormal proteins for cellular protection. Generally, the proteasome targets substrate proteins that are marked by attachment of multiple ubiquitin molecules. In various types of cells in an organism, damage to proteins occurs both from internal sources such as reactive oxygen species and from external ones such as UV radiation from the sun. The proteasome functions to protect the cells by degrading damaged proteins...

Mitochondria are subcellular organelles present in most eukaryotic cells which play a significant role in numerous aspects of cell biology. These include carbohydrate and fatty acid metabolism to generate cellular energy through oxidative phosphorylation, apoptosis, cell signalling, haem biosynthesis and reactive oxygen species production. Mitochondrial dysfunction is a feature of many human ageing tissues, and since the discovery that mitochondrial DNA mutations were a major underlying cause of changes in oxidative phosphorylation capacity, it has been proposed that they have a role in human ageing...

Development from embryo to adult, organismal homeostasis and ageing are consecutive processes that rely on several functions of the nuclear envelope (NE). The NE compartmentalises the eukaryotic cells and provides physical stability to the genetic material in the nucleus. It provides spatiotemporal regulation of gene expression by controlling nuclear import and hence access of transcription factors to target genes as well as organisation of the genome into open and closed compartments. In addition, positioning of chromatin relative to the NE is important for DNA replication and repair and thereby also for genome stability...

Nuclear structure influences genome architecture, which contributes to determine patterns of gene expression. Global changes in chromatin dynamics are essential during development and differentiation, and are one of the hallmarks of ageing. This chapter describes the molecular dynamics of chromatin structure that occur during development and ageing. In the first part, we introduce general information about the nuclear lamina, the chromatin structure, and the 3D organization of the genome. Next, we detail the molecular hallmarks found during development and ageing, including the role of DNA and histone modifications, 3D genome dynamics, and changes in the nuclear lamina...

We outline the progression of ageing research from ancient history to present day geroscience. Calorie restriction, genetic mutations, and the involvement of the sirtuins are highlighted, along with pharmaceutical interventions, in particular rapamycin. At the cellular level, replicative senescence and telomere shortening are presented in the history of ageing studies. We discuss the roles of macromolecular damage in ageing including damage to nuclear, and mitochondrial DNA, epigenetic and protein damage...

Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein-folding, quality control and function. In particular, the heat-shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein-folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease...

Protein homeostasis relies on a balance between protein folding and protein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfill well-defined roles in protein folding and conformational stability via ATP-dependent reaction cycles. These folding cycles are controlled by associations with a cohort of non-client protein co-chaperones, such as Hop, p23, and Aha1. Pro-folding co-chaperones facilitate the transit of the client protein through the chaperone-mediated folding process. However, chaperones are also involved in proteasomal and lysosomal degradation of client proteins...

Posttranslational modifications (PTMs) regulate myriad cellular processes by modulating protein function and protein-protein interaction. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone whose activity is responsible for the stabilization and maturation of more than 300 client proteins. Hsp90 is a substrate for numerous PTMs, which have diverse effects on Hsp90 function. Interestingly, many Hsp90 clients are enzymes that catalyze PTM, demonstrating one of the several modes of regulation of Hsp90 activity...

Mitochondrial J-domain protein (JDP) co-chaperones orchestrate the function of their Hsp70 chaperone partner(s) in critical organellar processes that are essential for cell function. These include folding, refolding, and import of mitochondrial proteins, maintenance of mitochondrial DNA, and biogenesis of iron-sulfur cluster(s) (FeS), prosthetic groups needed for function of mitochondrial and cytosolic proteins. Consistent with the organelle's endosymbiotic origin, mitochondrial Hsp70 and the JDPs' functioning in protein folding and FeS biogenesis clearly descended from bacteria, while the origin of the JDP involved in protein import is less evident...