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Biomarkers of Aging

What Is Loss Of Proteostasis? – The Hallmarks Of Ageing Series

Posted on 26 May 2021

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In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.

The Hallmarks of Aging: Cell
The hallmarks of ageing.

What Is Proteostasis?

Our cells are extremely efficient and effectively regulated, putting most human logistical endeavours to shame in their complexity and capacity for recycling and self-maintenance. Each ribosome (the protein factories of the cell) receives instructions from transcribed genetic information, and assembles amino acids (the building blocks of proteins) together to produce the thousands of different proteins we have in our bodies. These strings of joined amino acids rearrange themselves into an overall 3-D structure determined by the amino acid sequence. This rearrangement is sometimes aided by proteins called chaperones, which help other proteins to arrange themselves in the conformation necessary for them to function properly.

Proteostasis is essentially the overall ‘management’ of proteins, including building them correctly when they are needed, their continued maintenance, shuttling them around the cell and recycling/destroying them once they’ve become too damaged to do their job properly. Careful regulation of these processes is extremely important to the cell. We have evolved to be thrifty with energy and cannot afford to keep making endless proteins that we don’t need – they’ll simply clog up the cell and cause damage. Our situation is constantly changing and an appropriate balance of creation, maintenance and recycling of proteins is key to keep our cells healthy and functioning.

IJMS | Free Full-Text | Proteostasis and Proteotoxicity in the Network  Medicine Era | HTML
Protein synthesis and degradation must be balanced to keep cells functioning efficiently.

Cells possess a number of systems to maintain proteostasis:

  • Chaperone proteins are able to guide a new protein into the desired structure or to disassemble and re-fold those that have adopted an incorrect structure (misfolding) or have lost their structure. Misfolding is potentially dangerous to the cell and can cause aggregates to form when misfolded proteins clump together.
  • Proteasomes and the lysosomes act as molecular waste disposal systems, digesting proteins into their constituent parts:
    • Proteasomes exclusively break down proteins that have been tagged with a molecule called ubiquitin. Proteasomal digestion yields short amino acid chains which, if required, can be further broken down into individual amino acids.
    • Lysosomes are filled with strong hydrolytic enzymes that degrade all kinds of biomolecules. Chaperone proteins can guide smaller proteins to a lysosome to be digested, but lysosomes are also able to break down entire organelles such as faulty mitochondria (the organelles that provide energy for the cell).
  • Proteases break down damaged and misfolded proteins outside of the cell. Proteases are enzymes that cells secrete into the extracellular matrix (the ‘meshwork’ of proteins that fills the space between cells and holds them together). There, proteases break down damaged proteins into to smaller pieces that can then be taken up by cells for further degradation.
  • Stress-activated mechanisms help protect proteostasis against stimuli that may promote protein damage, such as temperature changes and radiation. For example, heat shock proteins help stabilise other proteins and encourage re-folding in response to temperature changes (which can encourage our enzymes to unfold or change shape), ultraviolet light, pathogens or tissue damage.

An introduction to loss of proteostasis by the American Aging Association

How Is Ageing And Loss Of Proteostasis Linked?

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The potential fates of an unfolded protein: misfolding and aggregation; refolding by chaperone proteins; degradation by proteosome; degradation by lysosome.

This balancing act of proteostasis is usually very well organised and regulated in response to different situations. However, proteostasis seems to become dysregulated with ageing. At the same time, exposure to sources of damage, such as reactive oxygen species produced by the cell’s own metabolism, increases during ageing. Consequently, the workload of repairing damaged proteins can become too great for the cell to handle. When the rate at which proteins are misfolding outstrips that at which they can be refolded, problems begin to arise. Misfolded proteins form aggregates as mentioned earlier, and these are implicated in a range of illnesses – perhaps most famously in neurological conditions such as Alzheimer’s and Parkinson’s disease.

Another major problem that is worsened by a loss of proteostasis is glycation. Glycation is a specific form of protein damage in which a sugar molecule reacts with a protein, forming what is known as an advanced glycation end product (AGE). AGEs can link two proteins together and further disrupt their function. Under normal circumstances protein turnover within cells is too fast to allow AGEs to accumulate, but some proteins outside the cell such as collagen can have a turnover rate of up to 10 years. Over time, more regions of these proteins are glycated, making them progressively harder to remove. Glycation contributes to serious medical complications such as nerve damage, blindness and heart disease. It also plays a major role in skin ageing, as AGEs form cross links between elastin and collagen proteins, resulting in a loss of elasticity and firmness. Diabetes sufferers are exemplars of glycation in its extreme, as they are unable to efficiently control blood sugar levels and so suffer a vastly increased rate of glycation.

The inability to sufficiently remove particular types of molecules via the proteasome or lysosome also begins to pose a problem with age. When lysosomes begins to struggle with their workload, they may accumulate molecules which dilute their acids and digestive enzymes, worsening the problem. Eventually the organelle can rupture and release its toxic contents into the cell. With age there is generally a significant accumulation of lipofuscin (also called age pigment), which is effectively a catch-all term for lipid containing residues that the cell is unable to degrade. This accumulation is both the consequence and a sign of the failure of proteostasis. This ‘clogging’ of the cellular waste disposal system ultimately makes it harder for the cell to clear waste that really matters, such as protein aggregates and damaged proteins and organelles.

The Early History of Autism Research: John K. Darby, MD | Cortical  Chauvinism
Image showing the accumulation of lipofuscin in a neuron.

How Can Loss Of Proteostasis Be Measured?

Loss of proteostasis has a great many potential manifestations that can be measured. Various molecular probes can be used to measure the misfolding and aggregation if proteins in cultured cells. This is possible because inaccessible regions located at the core of the protein may be exposed and able to be targeted by probes when the protein has folded incorrectly. Genetic techniques can also be used to modify proteins of interest so that they fluoresce or show enzymatic activity, but only when correctly folded.

Fig. 1
Strategy for assaying protein foldedness via access to buried cysteine thiols.

In living humans, manifestations of loss of proteostasis that might be measured include protein aggregation, glycation and lysosome dysfunction. A wide range of approaches exist for measuring these depending on circumstance. They include fluorescence techniques, positron emission tomography (PET) imaging, measurements of enzymatic activity and simple microscopic observation of cells and tissues.

How Might Loss Of Proteostasis Be Fixed?

Loss of proteostasis appears to be a common feature of ageing, and there is genetic and pharmacological evidence from animal models that not only can loss of proteostasis be reversed, but that doing so can delay aspects of the ageing process and prolong life. In particular, there is interest in enhancing autophagy (the clearance of damaged organelles by lysosomes) as a treatment that could promote longevity. We already know of multiple compounds, such as rapamycin and spermidine, that promote longevity in fruit flies, worms and mice by enhancing autophagy. There is some research suggesting that these compounds can slow ageing in humans, but more studies are needed.

While the formation of protein aggregates is associated with ageing and the development of age-related diseases, most notably neurodegenerative diseases, the extent of its causal role in these conditions and in normal ageing is still not entirely clear. For example, some people with significant levels of protein aggregation in the brain still suffer relatively little cognitive decline, and while neurodegeneration can be accelerated in animals by accelerating protein aggregation, treatments aimed at removing aggregated proteins in humans have shown no substantial benefits in the treatment of neurodegenerative disease. This suggests that targeting protein aggregation might be a less fruitful avenue for reversing ageing than many other approaches.

Reversing glycation and undoing the formation of advanced glycation end-products (AGEs) may be an effective strategy for slowing or reversing ageing, as glycation is a common link that promotes all hallmarks of ageing. For example, glycation can damage DNA and contribute to genomic instability. However, in order to fully establish the importance of glycation in the ageing process, we need tools that can reverse the formation of AGEs, and until relatively recently such tools did not exist. As techniques for reversing glycation improve, so too will our understanding of the importance of glycation and whether its reversal might yield meaningful longevity benefits.

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    The Hallmarks of Aging:

    Autophagy and Longevity:

    Spermidine delays aging in humans:

    Amyloid and Tau Pathology in Normal Cognitive Aging:

    Biocatalytic Reversal of Advanced Glycation End Product Modification:

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