Fight Aging!

In order to function correctly, proteins must form a specific folded structure after assembly from amino acids in a ribosome. This folding doesn't always work as it should, and there is naturally some rate of error for processes taking place in the crowded, organized chaos of a cell interior. Protein misfolding leads to non-functional, sometimes toxic molecules. In the worst case scenario, with only a handful of proteins in the body being capable of this, a misfolded protein can encourage other molecules of the same protein to also misfold, and join into solid aggregates. Beyond this, a given error rate in folding across all proteins produced by a cell puts stress on that cell, and is addressed by a variety of quality control and housekeeping mechanisms that flag and recycle such mistakes when they occur.

To what degree is the burden of misfolded proteins an important mechanism of aging? The handful of well-known misfolded proteins that can spread from cell to cell and form solid aggregates, such as amyloid-β and α-synuclein, are a characteristic feature and likely important contributing cause of age-related neurodegenerative conditions. But beyond these few types of protein, is there a background of diverse misfolded proteins that builds up with age to cause broad cellular dysfunction, particularly in long-lived cells such as neurons? In today's open access paper, researchers argue that this is likely the case, based on data from a range of species. They identify a few hundred different proteins in which the presence of misfolded molecules appears to increase with age.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence

The biological activity of cells and organisms depends on the proper function of many different proteins involved in key cellular signaling pathways. To remain biologically active, proteins need to preserve their native three-dimensional structure and solubility. Any alterations to these parameters challenge their ability to perform their normal biological function, with devastating consequences for the cell and the organism. Previously reported evidence showed a transition to insolubility of several proteins during aging in different models. Interestingly, many of these proteins are predicted to have high propensity to misfold and aggregate, similarly to protein misfolding disorders (PMDs). Based on these observations, we hypothesized that during aging several different proteins undergo progressive misfolding and aggregation to form structures similar to those found in age-related PMDs, causing widespread and chronic cellular dysfunction, which is the hallmark feature of aging.

In this study, we report the extensive and progressive accumulation of misfolded proteins during natural aging/senescence in different models, in the absence of disease. We coined the term age-ggregates to refer to this subset of proteins. Our findings demonstrate that age-ggregates exhibit the main characteristics of misfolded protein aggregates implicated in PMDs, including insolubility in detergents, protease-resistance, and staining with dyes specific for misfolded aggregates. Misfolded protein aggregates with these characteristics are thought to be implicated in some of today most prevalent diseases, including Alzheimer's disease and related forms of dementia, Parkinson's disease, Amyotrophic Lateral Sclerosis, type 2 diabetes, and even cancer. The strongest risk factor for all these diseases is aging, supporting our concept that advanced age is associated with increased accumulation of misfolded protein aggregates.

We found intracellular age-ggregation in the aged brain, where misfolded proteins are sequestered into aggresomes. Aggresomes have been studied in the context of neurodegenerative diseases, where they act as a general defense mechanism against high levels of accumulation of toxic misfolded proteins. Our results indicate that the aged brain contains relatively large amounts of misfolded species, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. By comparison with PMD, it is likely that the aging-associated misfolded protein will be non-functional or acquire a toxic activity. Therefore, we speculate that age-related protein misfolding may play a key role in the decline of those processes. Alternatively, the formation of misfolded aggregates might be a consequence of a dysfunctional proteasomal and other degradation pathways. The reproducibility of our results using various different techniques, methodologies, and model systems (invertebrates, cellular models, and rodents) indicate that protein misfolding during aging is not a stochastic phenomenon, but rather that a specific subset of proteins are prone to misfold with age.