Senescence-delaying factors; senescent cell (Dall-e)

Health

An unusual attribute of senescence-inducing factors

By Juman Hijab

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Original date: August 17, 2023  

Updated: August 31, 2023

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Senescence-delaying factors; senescent cell (Dall-e)

Senescent cell (Courtesy of Dall-e)

Senescence and proteins of aging

In a previous article, I highlighted how proteins of aging seem to localize on the basolateral aspect of the membrane. In this article, I will highlight a characteristic that seems to characterize the factors that bind to those basolaterally-localized proteins of aging. These are the senescence-inducing factors. 


Senescence-inducing factors bind to the basolateral membrane proteins and set off a cascade of effects that can lead to cell senescence. On the flip side, there are factors that have the opposite effect; that is, they seem to protect the cells (and the organism) from aging. In a future article, I will contrast senescence-inducing with senescence delaying factors.

Aging and senescence-inducing factors

As I discussed in earlier articles on senescence and senescence-inducing factors, there are biochemical actors that can turn to the dark side and play havoc with the cytoplasm's normal metabolic functions. This is particularly true when those factors are present in high levels in the plasma (12).


For example, interleukin-6 (IL-6) and Tumor Necrosis Factor alpha (TNF alpha) levels are increased in older individuals and the higher levels correlate with disability and disease in the elderly (2). In contrast, Japanese centenarians have lower levels of those pro-inflammatory factors.

The protein's isoelectric point

Specialized proteins (like cytokines and growth factors) clearly have a good side. They regulate cell growth, differentiation, and survival. Each protein has a specific isoelectric point (pI). This point is the pH (fluid acid or H+ level) at which the protein has no net charge.


Thus, a  basic protein (with lots of lysine and arginine amino acids) will have a high isoelectric point, as the pH at which the basic amino acids have no charge has to be much more basic. Conversely, an acidic protein has a low pI because it needs an acidic pH to have neutralization of the acidic (like glutamic and aspartic acid) amino acids.

Senescence-delaying proteins; arginine
Senescence-delaying proteins; glutamic acid

Bioreg images.  Arginine (left) and Glutamic Acid (right). Flickr.com, Aug 20, 2011.

In the plasma, which has a pH ~ 7.4, a protein with a high pI will have protonated amine (NH3+) moieties on their basic amino acid side groups. Conversely, a protein with a low pI will have a lot of deprotonated carboxylate (COO-) moieties in their acidic amino acid side groups.


The pI determines the overall character of a protein: its ability to interact with other molecules, including cell surface receptors, its stability, its protein folding, and its solubility in different parts of the cell (3, 4). Moreover, the pI of the protein determines where proteins end up: For example, the more acidic proteins end up in acidic compartments and the more basic proteins end up in the nucleus and the mitochondria (4).


Let's look at the isoelectric points of senescence-inducing proteins.

Pro-inflammatory proteins (senescence-inducing)

Senescence-inducing cytokines (signaling proteins in the immune system) and growth factors tend to have an acidic pI. This suggests that the acidic charge of these proteins may contribute to their ability to induce senescence. For example, tumor necrosis factor-alpha (TNF-alpha) has an acidic pI of 5.8. TNF-alpha is a pro-inflammatory cytokine that has been shown to induce senescence in cells.

The table shows several examples of senescence-inducing cytokines. Note that all but one have an acidic pI (under 7.0). The one factor with a basic pI (Fas Ligand) has a 26 amino acid segment that is more acidic than basic; it is this segment that calls the shots for the Fas Ligand.

Let's look at the example of a senescence-inducing factor (that is not a protein) with an extremely low pI: lipopolysaccharide (LPS). This molecule is a major component of the outer membrane of Gram-negative bacteria. It is a potent endotoxin, which means that it can cause inflammation and other harmful effects when it enters the bloodstream. It has a pI of ~2.5.

LPS  was studied in lung alveolar cells (that line the airways). This pro-inflammatory factor induces senescence in cells and hinders tissue repair (5).

Senescence-inducing factors: Pro-inflammatory factors

Senescence-inducing factors: Pro-inflammatory factors

In this table, I also highlight where the protein receptor that binds to those pro-inflammatory factors is localized. In all instances, those pro-inflammatory protein receptors are localized to the basolateral part of the plasma membrane. This is a main tenet of the process that engenders senescence. In a future article, I will go over why localization of proteins on the basolateral aspect of the cell leads to senescence of the cell.

Juan Gaertner. Different membrane proteins: (left to right) Potassium channel, delta-opioid receptor, LDL receptor, acetylcholine receptor, histamine receptor. The LDL receptor has a large extracellular segment and is typically localized to the basolateral membrane (6). Shutterstock, 1090429940.

Conclusion and further reflection

Senescence is a state of permanent cell cycle arrest that is characterized by a number of changes in gene expression and metabolism. Senescent cells can secrete harmful molecules that can damage other cells and tissues.

In this article I highlight an interesting observation: 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. 

Related articles in this series

  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: 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 (this article): 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. 

References for article

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  4. Kiraga, J., Mackiewicz, P., Mackiewicz, D. et al. The relationships between the isoelectric point and: length of proteins, taxonomy and ecology of organisms. BMC Genomics 8, 163 (2007). https://doi.org/10.1186/1471-2164-8-163.
  5. Kim CO, Huh AJ, Han SH, Kim JM. Analysis of cellular senescence induced by lipopolysaccharide in pulmonary alveolar epithelial cells. Arch Gerontol Geriatr. 2012 Mar-Apr;54(2):e35-41. doi: 10.1016/j.archger.2011.07.016. Epub 2011 Aug 25. PMID: 21871670.
  6. Yokode M, Pathak RK, Hammer RE, Brown MS, Goldstein JL, Anderson RG. Cytoplasmic sequence required for basolateral targeting of LDL receptor in livers of transgenic mice. J Cell Biol. 1992 Apr;117(1):39-46. doi: 10.1083/jcb.117.1.39. PMID: 1556156; PMCID: PMC2289410.

References for table

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  2. Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. doi: 10.1242/jcs.113.20.3593. PMID: 11017875.
  3. Abdolalizadeh J, Majidi Zolbanin J, Nouri M, Baradaran B, Movassaghpour A, Farajnia S, Omidi Y. Affinity Purification of Tumor Necrosis Factor-α Expressed in Raji Cells by Produced scFv Antibody Coupled CNBr-Activated Sepharose. Adv Pharm Bull. 2013;3(1):19-23. doi: 10.5681/apb.2013.004. Epub 2013 Feb 7. PMID: 24312807; PMCID: PMC3846060.
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  5. Kajikawa O, Herrero R, Chow YH, Hung CF, Matute-Bello G. The bioactivity of soluble Fas ligand is modulated by key amino acids of its stalk region. PLoS One. 2021 Jun 17;16(6):e0253260. doi: 10.1371/journal.pone.0253260. PMID: 34138914; PMCID: PMC8211282.
  6. Yamada A, Arakaki R, Saito M, Kudo Y, Ishimaru N. Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance. Front Immunol. 2017 Apr 5;8:403. doi: 10.3389/fimmu.2017.00403. PMID: 28424702; PMCID: PMC5380675.
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  8. Tumor necrosis factor ligand superfamily member 6/CD95/Fas ligand: isoelectric point = 9.41
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Tags

aging, cells, inflammation, senescence


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