Curious Cook: Ageing and the citrate connection


Cutting down on sugary foods is ideal for a healthy diet and to prevent the effects of age-related inflammation. — MCCUTCHEON/Pexels

My peers and I are now at an age when ageing and health issues concern us a lot more than before. The problem with ageing is that (a) one must be remarkably brave to grow old, and (b) ageing is a much more complicated process than most of us had ever assumed.

As we age, our bodies undergo numerous changes at the cellular level that contribute to declining health and increased susceptibility to disease. These changes are mostly related to diets and lifestyles, but research has established there is also another important underlying process which increases with age.

One key player in this process that scientists have recently uncovered is an enzyme called ATP-citrate lyase, or ACLY. This relatively obscure molecule appears to play a prominent role in driving age-related inflammation and shaping the biological environment within senescent cells or zombie-like cells that have stopped dividing but somehow still refuse to die.

An introduction to SASP

To understand ACLY’s importance, we first need to understand cellular senescence. As cells accumulate damage over time or in response to stress, some enter a state of permanent growth arrest called senescence.

While cell senescence can help suppress tumour formation, such cells sometimes do not quietly retire and die (as they should). Instead, they begin pumping out a potent cocktail of inflammatory molecules, growth factors, and other signalling proteins. This reaction produces a set of observable characteristics known as the senescence-associated secretory phenotype, or SASP.

The SASP behaves like a double-edged sword. Short term, it can usefully promote wound healing and help clear some damaged cells. But chronic exposure to SASP eventually creates a pro-inflammatory environment linked to many age-related diseases.

Indeed, the accumulation of senescent cells and their inflammatory secretions in tissues is now recognised as a clear hallmark of ageing. Humans simply accumulate more senescent cells due to ageing, resulting in more SASP. And SASP contributes to chronic, low-grade inflammation throughout the body – a state some researchers call inflammaging.

ACLY

This is where ACLY enters the picture. Recent research has revealed that this enzyme plays a crucial role in enabling senescent cells to produce their inflammatory secretions. ACLY is responsible for generating acetyl-CoA, an important intermediate metabolic molecule, from citrate in a normal cell’s cytoplasm (the liquid mix of water, salts, proteins, DNA, etc, within the cell membrane).

ACLY activity and cytoplasmic acetyl-CoA production are significantly enhanced in senescent cells. This increase in ACLY activation appears to be a key driver of the pro-inflammatory SASP.

Scientists have discovered that blocking ACLY activity in senescent cells dramatically reduced their production of inflammatory factors like interleukin-1 and interleukin-8. Importantly, this occurred without affecting other hallmarks of senescence like growth arrest, suggesting ACLY specifically controls primarily the inflammatory component and subsequent processes. This is an important observation as it leads one to hope that controlling ACLY may slow down ageing.

Rewiring metabolism and gene expression

But how exactly does an increase in ACLY activity translate into more inflammation? The answer lies in the complicated intersection of metabolism and gene regulation.

Acetyl-CoA produced by ACLY serves as a substrate (or active cellular layer) for histone acetyltransferases. These are enzymes that add acetyl groups to histone proteins around which DNA is wrapped in a process called histone acetylation. Histone acetylation normally tends to activate genes and make them more accessible.

Technically, ACLY promotes increased histone acetylation specifically at the enhancers of pro-inflammatory genes. In simpler words, it means that ACLY can prise open or disrupt internal cell structures, creating new inflammatory gene enhancer attachment points. These ACLY-created points then allow for increased binding of cellular activation factors and other proteins into the cells’ DNA, RNA and associated proteins.

One key protein identified is BRD4, a special protein that recognizes acetylated histones and helps activate gene expression. The ACLY-dependent acetylation creates more binding sites for BRD4 at inflammatory gene enhancer points, further ramping up their activity.

A metabolic-epigenetic circuit

This creates a fascinating metabolic-epigenetic circuit. Epigenetics is the study of how behaviours and characteristics of cells change due to the influences of other molecules. With ACLY, increased citrate metabolism provides the raw material (acetyl-CoA) for histone modifications that then alter gene expression patterns. It is a prime example of how shifts in cellular metabolism can reprogram gene activity to drive ageing phenotypes.

An interesting aspect of ACLY is its specificity. That is because ACLY upregulation does not globally increase histone acetylation throughout the affected cells. Instead, ACLY seems to selectively target and promote only inflammatory gene enhancers. This suggests there are additional layers of metabolic regulation which affect ACLY activity. Basically, ACLY provokes a significant increase of only inflammatory genes, but the reasons why are currently not known.

Implications for age-related diseases

The discovery of ACLY’s role in driving the inflammatory SASP has wide-ranging implications for understanding and potentially treating age-related diseases. Chronic inflammation is a common thread linking conditions like cardiovascular disease, metabolic syndrome, neurodegenerative disorders, and various cancers.

Early research in addressing such ACLY-provoked inflammation is promising. Studies in mice have shown that inhibiting ACLY can improve metabolic health in obese rodents and enhance physical strength in ageing animals. Clinical trials are now underway to test ACLY inhibitors for treating various cancers and metabolic disorders.

A new target for anti-ageing interventions?

Could targeting ACLY be a way to slow ageing itself? It is an intriguing possibility, though much more research is needed as it is not always plausible to extrapolate findings from cellular studies to whole-organism ageing. However, one advantage of focusing on ACLY is its specificity. Unlike some proposed anti-ageing strategies that broadly eliminate senescent cells, the current research suggests that modulating ACLY activity could allow for a more targeted approach.

The bigger picture: metabolism and ageing

The ACLY story reflects a broader understanding of the ageing process. Increasingly, research points to alterations in cellular metabolism as key drivers of age-related decline. Many hallmarks of ageing, such as genomic instability, epigenetic alterations, chronic inflammation, etc, are inextricably linked to changes in how cells process nutrients and generate energy.

A low-fat diet free from red meat could help decrease the presence of the enzyme ACLY that drives age-related inflammation. — CATS COMING/PexelsA low-fat diet free from red meat could help decrease the presence of the enzyme ACLY that drives age-related inflammation. — CATS COMING/Pexels

This metabolic perspective opens new possibilities for anti-ageing strategies. Diet, exercise, and compounds that modulate metabolic pathways are all being explored as potential anti-ageing strategies. ACLY inhibition also appears to be profoundly influenced by dietary factors, and some such factors to consider are as follows:

1) Low-fat diet and calorie restriction

Reducing overall calorie intake, particularly from fats, may help decrease ACLY activity because ACLY plays a central role in the metabolism of fats and fatty acid synthesis. Therefore, a lower-fat diet (particularly avoiding fats from red meats) could reduce the availability of substrates for ACLY. Also, calorie restriction has been linked to increased lifespans and reduced cellular senescence in various studies, which is an interesting correlation.

2) Reduction of sugars

Glucose is a key substrate for ACLY, and cutting down sugars may decrease ACLY’s role in converting citrate to acetyl-CoA for fatty acid synthesis.

3) Omega-3 fatty acids

Omega-3 fatty acids have well-established anti-inflammatory properties that could counteract the pro-inflammatory environment of senescent cells triggered by ACLY. Foods rich in omega-3s include fatty fish, flaxseed, walnuts, and especially chia seeds, and these are all foods which are readily available.

4) Polyphenol-rich foods

Foods with polyphenols such as proanthocyanidins have been shown to regulate key enzymes involved in lipid metabolism, including ACLY. The richest sources of proanthocyanidins are grapes (including the seeds), apples and chocolate, so it is not onerous to add them to the diet.

5) Limiting refined carbohydrates

Refined carbohydrates such as processed flours and sugars are usually large collections of glucose molecules held together by weak glycosidic bonds. During digestion, the actions of digestive enzymes decompose such foods readily into pure glucose molecules, resulting in foods with very high Glycaemic Index (GI) readings. And high GI foods cause rapid spikes in blood sugar levels.

The obvious candidates to avoid are fizzy drinks, confectioneries, fruit juices, and most Ultra-Processed Foods (UPFs). Be especially wary of UPFs sold as “convenient” or even “healthy” foods, which includes white breads, breakfast cereals, cakes, snacks, etc.

High GI foods cause elevated glucose levels which in turn can increase lipogenesis, a process involving ACLY. Therefore, opting for complex or unrefined carbohydrates and low GI foods, especially those with high dietary fibre content, will help slow glucose metabolism. Examples include oats, organic brown rice, legumes, fresh fruits, nuts and seeds, etc.

6) AMPK activators

Dietary components that activate AMPK (AMP-activated Protein Kinase) may indirectly affect ACLY, because AMPK activation has been linked to reduced ACLY activity. There is a wide range of foods that promote AMPK activation, including green vegetables, green tea, fruits, berries, onions, olive oil, turmeric, legumes, apple cider, oily fish, etc.

It is also important to note that AMPK activation is significantly influenced by other factors, including but not limited to calorie restricted diets, adequate exercise, increased fibre intake, reduced UPF consumption, etc.

7) Cut down inflammation

Finally, consider minimising inflammation via a proper, balanced diet. This means not just a varied diet, but also avoiding eating too much delicious foods with highly inflammatory compounds such as Advanced Glycation End-products (AGEs). These AGEs are found in fried, roasted, grilled, baked, or aged foods, and they can provoke molecular-level responses in cells that increase cell senescence and enhanced ACLY activity.

The views expressed here are entirely the writer’s own.

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