Still, we did a lot of work at Open Genes. At the beginning of the year, we had 70 somehow described genes in the database, and now we have 477, described much better. We have probably become the largest and most well-structured database on the genetics of aging. Why is this necessary, besides the fact that it is extremely exciting to study how the genetics of aging works?
Usually scientists look at this or that important process in aging and say: “Let’s now intervene in it and find out if we can extend the life of a laboratory animal?”. They turn on or turn off some genes or their products and see if life extension has succeeded.
Our approach is simple: let’s take into account the change in the work of all genes associated with aging and life extension. Maybe we will find the best combination for gene therapy and get closer to the ideal work of the genome? We will turn on / off different genes at different times, preventing the animal from dying.
Here, of course, works for tens of millions of dollars.
To attract them, we want to structure the data even better in order to find the best principles for the selection of gene therapy.
Moreover, it is not at all necessary that we find the best combination. Maybe you will do it? Our task is to provide the most complete and understandable material on the topic. Describe what opportunities and challenges exist.
If the race to find the best combinations to extend life has not taken on a universal scale, then we ourselves have not yet finalized and must improve the Open Genes database and create new databases. There are many processes associated with aging in the body, and all of them should be described in databases.
Now hold on to our next story, about another cytoprotective gene whose product is associated with autophagy, aging, and tumorigenesis.
This is the TFEB gene , encoding the transcription factor EB.
TFEB is one of the key regulators of autophagy. For a better understanding of the age function of TFEB , let’s remember what it is.
Autophagy is the process of breaking down damaged structures to release amino acids and free fatty acids for protein synthesis and energy production. Autophagy is necessary to maintain the constancy of the intracellular environment: genes synthesize proteins all the time, they need to be put somewhere (proteins are not read from genes, but everyone knows this anyway).
Autophagy is a lysosomal-dependent pathway for the degradation of damaged intracellular structures.
(If I lost you here, then okay, go. You already read the main thing. Further it will be more difficult. If anything, the lysosome is a department in the cell that processes all kinds of crap. If it does not work perfectly, problems begin.)
In mammalian cells, autophagy is subdivided into macroautophagy, microautophagy, and chaperone-mediated autophagy.
Cell survival or death is determined by the degree of autophagy. Normal physiological levels of autophagy are relatively low and promote survival. Whereas insufficient or excessive levels contribute to cell death.
Autophagy acts as a protective mechanism of cells against adverse environmental factors. Dysregulation of autophagy is closely associated with many diseases.
Autophagy in cancer cells plays a dual role, suppressing or promoting the development of pathology.
Also, autophagy is involved in the degradation of abnormal proteins, preventing their accumulation in neurons. Impaired autophagy is associated with the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Impairments of autophagy itself are associated with the accumulation of cellular lipids, which leads to fatty liver and other metabolic diseases. For example, autophagy is required to maintain the structure, number, and function of pancreatic β-cells and protect them under stressful conditions.
So, lysosomes. This is the center of processing in cells, which are acid compartments filled with more than 60 different types of hydrolases in mammalian cells.
Lysosomes are primarily responsible for breaking down the substrates of endocytosis and autophagy, such as membranes, proteins, and lipids, into their essential components.
Digestion products are excreted from lysosomes by means of vesicles.
Lysosomes play a role in cellular metabolism, immunity, regulation of hormone secretion, and other processes.
For example, melanin secretion by melanocytes, reabsorption of bone tissue by osteoclasts, secretion of proteolytic enzymes by natural killer cells, regulation of cell membrane repair by calcium ions, antigen presentation by macrophages and B-lymphocytes are all associated with the activity of lysosomes.
Autophagic activity is known to decrease with age. And as expected, contributes to the accumulation of damaged macromolecules and organelles during aging.
In another3 recent work, scientists have shown a possible reason why one of the genetic variants of apolipoprotein E is associated with neurodegeneration and Alzheimer’s is due to its repression of FoxO3a in the brain. Because of what, both autophagy and mitophagy are disrupted (the same thing, but in relation to mitochondria).
So, we remembered everything, back to our hero, TFEB .
It belongs to transcription factors from the evolutionarily conserved MiT/TFE family . In vertebrates, this group is represented by 4 proteins: MITF, TFEB, TFE3 and TFEC .
In addition to the primary role of MiT/TFE proteins as key regulators of lysosomal function and autophagy, research shows their involvement in an ever-expanding list of cellular processes.
(By the way, the functions of many proteins are still completely unexplored)
These include: nutrient uptake, energy metabolism, endoplasmic reticulum stress response, mitochondrial and DNA damage, oxidative stress, innate immunity and inflammation, neurodegeneration and tumorigenesis.
The MiT/TFE proteins are well conserved through evolution. Their homologues are found in primitive metazoans such as Trichoplax and sponges. And orthologues in invertebrates are HLH-30 in Caenorhabditis elegans and Mitf in Drosophila melanogaster .
When cellular nutrition is abundant, active mTORC1 phosphorylates TFEB . Phosphorylated TFEB is isolated in the cytosol, bound by a special protein, and remains inactive.
Nutrient deficiency activates TFEB . After that, it moves to the nucleus, which leads to the activation of its target genes involved in lysosomal biogenesis and autophagy.
Oxidative stress and endoplasmic reticulum stress due to accumulation of misfolded proteins also cause TFEB to be activated and translocated to the nucleus. Where it in turn upregulates the expression of genes associated with lysosomes and autophagy to counteract the detrimental effects of stress.
And in the case of severe and prolonged stress , TFEB can also increase the expression of apoptotic genes, killing the cell.
The logic of TFEB is this: let’s try to fix everything, if it doesn’t work out, we’ll kill it.
With mitochondrial dysfunction, TFEB is also activated . Proteins of the TFEB family are key regulators of mitochondrial biogenesis (the process during which damaged mitochondria are removed and replaced with new ones).
Here, the action of TFEB is associated with another known regulator of mitochondrial biogenesis, PGC-1α.
TFEB and its related protein, TFE3, are also upregulated in response to genotoxic stress through a p53- and mTORC1-dependent mechanism. Which leads to cell cycle arrest or apoptosis, depending on the severity of DNA damage.
The important role of TFEB in the antibacterial and antiviral response of the body is also described. Moreover, some of the pathogens, such as Mycobacterium tuberculosis, purposefully suppress the expression of TFEB and its target genes by activating miRNAs that interrupt protein translation.
HIV has also learned to suppress TFEB by phosphorylation.
In general, it can be said that proteins of the MiT/TFE family in general and TFEB in particular act as sensitive sensors responsible for transcriptional rearrangements that allow cells to adapt to internal and external stresses.
In short, God himself ordered such a gene to be associated with aging.
In 2013, this became clear4: M. Hansen et al. were the first to show the direct involvement of a related TFEB gene in a nematode (ortholog), HLH-30 , in the regulation of longevity. They found that mutant worms with extended lifespans (modified for tor , eat-2 , daf-2 , clk , rsks-1 , and glp -1 , the life extension king genes) also had HLH-30 activated .
Overexpression in HLH-30 worms extended their lifespan by 20% compared to the control.
The team also documented increased TFEB protein levels in calorie-restricted mice compared to controls.
In a 2020 paper, R. Houtkooper and colleagues demonstrated that the reduction of mitochondrial translation by RNA interference targeting the mitochondrial ribosomal protein S5 ( mrps-5 ) in C. elegans increases lifespan. This happened due to activation of the mitochondrial response to misfolded proteins (UPR MT) and fragmentation of the mitochondrial network.
Characteristically, the increase in the lifespan of such worms depended on the activity of HLH-30 : its knockdown abolished life extension5.
In another study, scientists have shown that inhibition of the nuclear export mechanism enhances HLH-30 activity and autophagy, contributing to an increase in the lifespan of C. elegans and fruit flies6.
In addition, increased HLH-30-mediated autophagy made the worms more resistant to thermal and proteotoxic stres7.
Finally, C. Riedel and colleagues in their work showed8 that the TFEB orthologue , HLH-30 , affects life expectancy together with another transcription factor known for its effect on longevity, DAF-16 / FOXO . Together with it, contributing to stress resistance and an increase in life expectancy.
Well, as in the case of the previous CISD2 gene , TFEB also has a dual role in oncogenesis. It can both activate proapoptotic processes in response to DNA damage together with the oncosuppressor protein p53 and promote their survival by its overexpression in cancer cells9 10 11.
The picture is like this. The action of TFEB strongly depends on the stage and type of cells: in a healthy body, TFEB will protect against tissue degeneration, and in pathology it will protect degenerated cells.
Autophagy may play a detrimental role here. Lysosomal autophagy promotes cancer survival by breaking down toxic molecules and maintaining adequate nutrient intake.
Knockdown of TFEB reduces the viability of tumor cells while increasing caspase-3-dependent apoptosis.”
At the same time, its overexpression in macrophages is useful for clearing mutated cells. Tumor progression of breast cancer can be suppressed by overexpression of macrophage-specific TFEB by increasing the functional status of immune cells in the tumor microenvironment.
That is, in some cells in cancer , TFEB must be activated, while in others it must be suppressed.
Why doesn’t TFEB activate the self-destruction of cancer cells, if it can? Most likely, he does not see a large number of breakdowns in the DNA.
How to make TFEB aware that it is in a cancer cell? I dont know. Maybe something can mimic DNA breakage by binding to another oncogene. Well, this is our conjecture with you.