Science of Ageing Flashcards
What are the SENS Institute’s 7 Damage of Ageing categories?
7 Damage of Ageing categories are: Cell loss Cell Death-Resistance Cell Over-proliferation Intracellular “Junk” Extracellular “Junk” Tissue Stiffening Mitochondrial Defects The above seven-category formulation is descriptive, not prescriptive. However, the fact that no new categories of damage have been discovered since 1982, despite the dramatic progress in bioanalytical techniques since that time, suggests that any other categories accumulate too slowly to have any bearing on health within the contemporary human lifespan.
Describe Cell Loss
Cell Loss
The most straightforward damage category is the loss (death without replacement) of cells, either as a result of chronic injury or acute trauma, mediated by apoptosis, by autophagic cell death, and/or by necrosis. Such losses lead to tissue atrophy, compromising the function of the organs involved; examples include Parkinson’s disease, sarcopenia, autoimmune diabetes, and presbycusis. Therapy involves the introduction of stem or progenitor cells (and/or stimulation of the proliferation of endogenous progenitors), either systemically with the assistance of appropriate targeting mechanisms, or locally via a tissue-engineered construct.
Describe Cell Death-Resistance
Cell Death-Resistance
Conversely, the accumulation of excessive numbers of cells refractory to normal homeostatic apoptosis can also be harmful. The most obvious example in the context of Western societies is obesity, but there are more subtle manifestations; the imbalance between anergic and naïve T-lymphocytes that characterizes immunosenescence being a prime example. Treatment is in this case conceptually straightforward; identify biomarkers that selectively target the undesirable cells, and deliver cytotoxic drugs or viruses to ensure their destruction.
Describe Cell Over-proliferation
Cell Over-proliferation
This deals with damage to the genomic DNA, in the form of mutation (changes to the base-pair sequence) and epimutation (changes to the moieties that decorate the DNA molecule and influence its transcription). Fortunately, this is one area in which evolution has done most of the hard work for you. Since the emergence of vertebrates (at least), the most serious problem originating from mutation has been cancer, which has the capacity to kill an organism if one single cell acquires enough mutational load, whereas any other mutation can in general become lethal only if it afflicts a substantial proportion of the cells in a given tissue. The proofreading mechanisms evolved to prevent cancer are, as a result, more than sufficient to keep non-cancerous mutations under control. Thus, this strictly molecular category of damage is in fact best treated as a cellular one.
Describe Intracellular Junk
Intracellular Junk
While cells are generally very efficient in detecting (particularly via the unfolded protein response) and recycling damaged or surplus biomolecules, there are some exceptions; substances which are genuinely refractory to degradation or excretion. The resulting accumulation of “junk” compromises the cell’s metabolism, at best impairing its normal function, and at worst leading to cell death. The accumulation of lipoproteins in atherosclerotic plaques and the phototoxicity of A2E that drives dry macular degeneration are two of the best-studied examples of this mechanism, which may be treated by augmenting the native degradation machinery by introducing novel enzymes capable of tackling the most recalcitrant targets. Such enzymes typically need to be introduced into the lysosome, cells’ “garbage disposal machinery of last resort.”
Describe Extracellular Junk
Extracellular Junk
Not all waste products accumulate within the cell; the infamous amyloid plaques of Alzheimer’s disease, as well as the amyloids associated with type II diabetes and systemic amyloidosis, accumulate in the extracellular space. Fortunately, the body already possesses an excellent mechanism for removing undesirable substrates from this compartment; the phagocytic cells of the immune system, and thus the elimination of this junk is essentially a problem of developing an effective and safe vaccine. (In a few cases, it may be necessary to apply the principles of the previous category, lysosomal enhancement, to ensure that the immune cells are able to fully degrade the substances they consume.)
Describe Tissue Stiffening
Tissue Stiffening
Protein comprises the bulk of the extracellular matrix; in many cases the proteins involved are laid down in early life and then recycled very slowly, if at all, in adulthood. The function of the tissues supported by such proteins, such as the elasticity of the artery wall, is dependent on their maintaining the correct molecular structure. As the years pass that structure becomes progressively compromised, primarily due to crosslinking induced by reactive molecular species, especially a network of reactions initiated by circulating sugars and collectively termed “glycation.” In the arteries, this stiffening leads to increasing blood pressure and all its downstream consequences. Fortuitously, such crosslinks are chemically distinct from any that are enzymatically derived, and the therapeutic strategy is thus to develop drugs or enzymes capable of cleaving these crosslinks to restore the original biophysical function.
Describe Mitochondrial Defects
Mitochondrial Defects Mitochondrial DNA (mtDNA) is uniquely vulnerable, being in close proximity to an intense source of reactive species (the respiratory chain) while lacking many of the sophisticated repair mechanisms available to nuclear DNA. There is a well-established accumulation of damage to mtDNA associated with aging, linked, as one would expect where such a vital cellular component is involved, to a very broad range of degenerative conditions. However, of the thousand or so protein components of a mature mitochondrion, only thirteen are actually encoded in the mtDNA, the remaining genes having moved over evolutionary time to the nuclear DNA, from where their products are efficiently translocated back to the mitochondrion. The solution in this case is thus not to repair damage to the remaining genes, but rather to introduce translocation-ready variants of them into the nuclear genome, a technique termed allotopic expression, obviating the issue of maintaining the mtDNA itself.
Describe what happens in Telomerase
The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy.
