A cure to aging

by | Feb 1, 2021 | Genetics, Science

We can imagine the generic cell as a small ball enclosed by a membrane (plasma membrane), containing the cytoplasm (a watery solution with salt ions, respiratory gases, proteins, sugars, and fats) and the organelles (small vesicles that are responsible for carrying out the main vital functions of the cell the same way organs do in the human body). Each cell receives orders about what to do during its life from DNA, a code of information and instructions locked in the nucleus. DNA is a large strand that contains everything cells need to do their work and produce the needed components.

Each cell, after birth, differs in form and function from the others according to its role, described by DNA. During cell growth, many areas of the DNA are inactivated because they are not useful for a specific function (For example a muscle cell does not need to produce anti-acid mucus as the cells of the stomach wall). An adult skeletal muscle cell is called a myofibril. It has a very elongated shape and is capable of contracting, generally, these cells fuse together to form large cellular complexes called syncytia (Myofibrils).

Myofibrils are organized into muscle fibers, surrounded by a protective membrane called the endomysium; multiple fibers are joined into fascicles, surrounded by the perimysium, while the entire muscle is protected by the epimysium. In between these muscle bundles are small populations of non-contractile stem cells, called satellite cells. These cells are used to replace damaged cells since muscle fiber cannot divide and regenerate itself (it is part of a cellular syncytium, fused to other cells).

Cell division is limited

Some cells in our body (such as neurons or muscle cells) never divide

When a cell needs to divide into two cells, it momentarily suspends its functions and makes a copy of all of its DNA. Unfortunately, in this process, a small portion is lost, due to a molecular limitation of DNA polymerases (the enzymes that copy DNA).
Each time the cell divides, the DNA shortens, until it loses functions that are very important to the survival of the cell. At some point, the DNA is so damaged that the cell is eliminated because it is no longer able to continue its task.
This is part of the cellular aging process.

Some cells in our body (such as neurons or muscle cells) never divide.
That is because cell division requires the cell to have a spherical shape: if a neuron detached itself from all its synapses to divide the result would be disastrous, also because then it could not reattach itself to them.
Muscle cells are so connected to each other that they are fused, so it is not even possible to distinguish one cell from the others: if they detached to divide, the muscle would lose functionality.

Special support groups, called satellite cells, exist for these cells.

The satellite cell

Viable in the body until a very old age, when at some point they differentiate

Satellite cells are groups of undifferentiated cells that retain stem cell status. Stem cells are undifferentiated cells that can become any cell type.
These groups of cells are normally quiescent and become activated when the tissue in which they are located suffers damage, in order to replace the damaged cells. 

In muscles, these cells do not have the contractile capacity, like muscle fibers, but they do have the proliferative capacity. Each time they divide they give birth to another stem cell and a cell that will differentiate until it becomes functional. These cells remain viable in the body until a very old age, when at some point they differentiate permanently and can no longer replicate themselves, hence effectively becoming muscle cells.

Other causes for cell aging

Cells change their activity based on molecular signals

In addition to the progressive shortening of the genome, cells change their activity based on molecular signals sent by other cells.
These signals can turn off or on different genes (the individual instructions contained in DNA) or even induce programmed cell death, called apoptosis.

In the case of skeletal muscle satellite cells, the molecular signal is called IGF1-dependent nickel-derived Akt, abbreviated as Akt.
Akt acts by inactivating the FoxO factor, another molecular signal by which the CD34 gene maintains the stem character of the cell.

Differentiation

Once the cells enter the primary differentiated state, they cannot become stem again

When the FoxO factor is inactivated, the CD34 gene is inactivated as well.
Cells at this point can be grouped according to expression, resulting in a group with the active gene (CD34High), which retains the stem character, and a group with the suppressed gene (CD34Low), which instead is defined as primarily differentiated.

Once the cells enter the primary differentiated state, they cannot become stem again, unless external intervention occurs.

This happens at a very late age, but it compromises muscle regeneration and, more generally, leads to weakened muscle.

Lab Methods

One of the main ones is fluorescence, a harmless method that does not harm the animal

Laboratory methodologies have been based on the collection of data from many groups of individuals.
Initially, the activity and vital state of cells in vivo (in living individuals) are monitored; subsequently, the development of cells from birth to adulthood is studied.

One thing must be emphasized: an analysis for gene activity is not limited to data collection of the activity of that single gene. A gene is regulated by other genes, it influences other genes, the protein derived from that gene interacts with other proteins within the cell … in such an analysis you study the activity of at least a dozen genes, including their transcripts (DNA can not leave the nucleus, so it needs a molecule that acts as an intermediary, RNA). 

The techniques used can be very different, one of the main ones is fluorescence, a harmless method that does not harm the animal and allows to follow the activity of a gene through the detection of fluorescence.

Conclusions

By working on the inhibition of Akt we can combat muscle aging, promoting an increase in quality of life

In aged mice, gene activity is maintained until very old age; what gradually declines is the number of satellite cells.

Satellite cell activity is maintained by the concentration of FoxO and Akt. The higher the concentration of FoxO the healthier the stem cells are, the higher the concentration of Akt (antagonist of FoxO) the more the cells differentiate definitively.

As age progresses, the number of cells decreases and Akt fights the action of FoxO.

By working on the inhibition of Akt we can combat muscle aging, promoting an increase in quality of life and independence in the elderly.

The FoxO discovery is announced in research published Oct. 26, 2020, in Nature Cell Biology.

References

García-Prat, L., Perdiguero, E., Alonso-Martín, S. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat Cell Biol 22, 1307–1318 (2020).

FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age

The second youth of muscles | Università La Sapienza