A salamander’s amazing secret for staying young: Destroy senescent cells

A salamander's power in maintaining youthfulness is related to three elements:

• The presence of adult stem cells in their body
• An innate ability to transform specialized adult cells into immature cells. 
• The ability to create a niche that is very conducive to regeneration

This means that - for salamanders - most of their specialized adult cells are an extensive treasure trove of cells that can be used to regenerate new tissues ((6, 7, 8, 9). 

Thus, experiments have been done where the lens of a Japanese Newt was removed. The newt was able to regenerate a new lens using retinal epithelial cells (7). Even old newts retained the ability to form new lenses. 

Stem cells are immature cells that have the ability to transform into new tissues. Interestingly, after a cell specializes or ages, the ball game is not lost.

Even in mammals, aged or specialized cells seem to have the ability to revert back to immature cells that display regenerative and reproductive abilities.

Giving an old cell new life

The trick is to give the nucleus of an old cell the appropriate youth stimuli. With that, an old cell can revert back to an immature state and regain the capacity for regeneration. For example,

• Dolly - the cloned sheep - was produced by putting an old nucleus into the cytoplasm of an enucleated fertilized ovum (8, 10).  
• Adding immaturity-inducing transcription factors to an old cell's nucleus (Yamanaka factors) can revert the cell back into a multi-functioning stem cell (8, 11)
• Vision loss was reversed in a mouse model of glaucoma by adding nuclear transcription factors (12)
• Parabiosis experiments (combining an old and a young mouse surgically to produce a single, shared physiological system) induced youthfulness in aged mice (13)

In each of those situations, an older cell is reprogrammed or encouraged to become youthful again. Young cells are the key to staying young.

Unfortunately, when stem cells age (or die and and are not replaced), the tissue/organism ages.

For example, geriatric muscle stem cells lose the ability to divide so that they can replace diseased muscle cells (6).  If that weren't enough, when cells become senescent, they create a "senescent" milieu around them. The nucleus changes its internal architecture and starts secreting proinflammatory proteins and encourages the extracellular matrix to remodel itself into an aged phenotype (6, 14). 

Unfortunately, this induces the nearby cells to become senescent. It is those changes that are thought to produce tissue degeneration, atherosclerosis, and loss of regenerative ability. (6).

Here's where the salamander has one up on  other animals. In mice and humans, senescent cells accumulate as the tissues age (3). Given that senescent cells beget more senescence, the development of aging-related conditions (atherosclerosis, loss of muscle mass, and  neurodegeneration) ensues.

Salamanders, on the other hand do not tack on senescent cells as they grow older. In fact, they have a highly active system to destroy senescent cells (14). The importance of getting rid of senescent cells to maintain youthfulness cannot be overstated. Experiments have shown that elimination of senescent cells decreases age-related pathology and leads to improved longevity in mice (15, 16). 

 These experiments have set the stage for multiple potential fountain of youth therapies in the rapidly expanding field of senotherapeutics. Clinical studies include the use of small molecules that target senescent cells (senolytics), drugs that delay the progression of young cells to senescent cells (senomorphics), and the use of the immune system to clear senescent cells from tissues (17, 18).