Senescent cells display unhealthy acidification of the cytoplasm

Proteins within the body have a narrow range of pH in which they function optimally. For example, albumin, a vital plasma protein that binds calcium, relies on a specific pH range for its activity. Hyperventilation, often triggered by anxiety, causes excessive removal of carbon dioxide (CO2), leading to respiratory alkalosis in the plasma.

This alkalosis reduces the number of hydrogen ions available to bind with albumin, allowing it to bind more calcium ions. Consequently, hypocalcemia occurs, leading to neuronal hyper-excitability, resulting in tingling sensations or muscle spasms (2, 3).

Normal adult neuron cells tend towards a more basic pH  (7.03 - 7.46 (3).

However, in neurodegenerative diseases there is abnormal acidification of the cytoplasm, which affects enzyme function within and outside the neuronal cell. In a previous article, I discuss the sequence of events that leads to lowering of cytoplasmic pH and neuronal death in Alzheimer's Disease. Just as in Alzheimer's disease, several neurodegenerative diseases also have abnormal acidification of the cytoplasm (5, 6). 

To add insult to injury, the extracellular space is also abnormally acidic in Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), and Huntington's disease (6).

Defective ATP production

The brain requires significant energy (20% of the body's energy despite being only 2% of its weight). Unfortunately, abnormal acidification of the cytoplasm leads to defective enzyme function and thus defective ATP production (7, 8). 

And to create even more havoc, defective ATP production leads to two more elements that compound the acidification of the cytoplasm:

• Generating ATP is one of the mechanisms that cells have for consuming H+ (through the mitochondrial proton gradient). Thus, defective ATP production exacerbates the acidosis (9).
• Dysregulated lysosomal acid processing contributes to the build-up of H+ ions within the cytoplasm. This is an early finding in neurodegeneration. Thus, not only are the dysfunctional neurons prone to producing lots of H+ ions in the cytoplasm, the lysosomes are not helping. They are not taking up H+ ions into their lumen, further worsening the acidification in the cytoplasm.

In fact, aging in experimental animals coincides with declining lysosomal acidity as well as a decline in the lysosome's ability to digest macromolecules (10, 11, 12).

Transient cytoplasmic acidification is a natural process for transmitting signals into cells. Growth factors and hormones, for instance, induce temporary H+ influx into the cytoplasm during signaling, after which the cell returns to its steady-state pH  (13, 14, 15).

On the contrary, experimental acidification of the intracellular or extracellular environment can induce senescence (16). High salt diets in transgenic mice lead to increased cytoplasmic acidification and subsequent early senescence and shortened lifespan  (17).

Unhealthy acidification of the cytoplasm arises from multiple pathways, setting cells on a path towards dysfunction and senescence.

 Understanding the complex relationship between pH regulation and cellular processes is vital for advancing our knowledge of aging and developing potential therapeutic interventions.

1.  Proteins of aging and their localization in the cell: Dysfunctional or hyper-functional membrane proteins that induce aging often reside in the basolateral regions of the cellular membrane.
2. Why it is important to learn about Senescence-associated secretory phenotype (SASP) proteins: Senescent cells accumulate over time and contribute to age-related diseases. They do this primarily by secreting Senescence-associated Secretory Phenotype (SASP) proteins. 
3. Senescent cells display unhealthy acidification of the cytoplasm (this article): There are multiple pathways all cascading to generate increased in cytoplasmic acid. These create a positive feedback loop that sets the cell up for a vicious cycle of dysfunctional intracellular organelles and ongoing  intracellular acidosis.
4. An unusual attribute of senescence-inducing factors: Pro-inflammatory factors tend to have more acidic isoelectric point, with more acidic side groups. The evidence suggests that there is a correlation between acidic side-groups, isoelectric point, and senescence-inducing factors.