Only 7 Pathogenic Age-related Precursors: Protein Crosslinks

One of the seven early precursors of age-related pathology are extracellular protein crosslinks, also known as advanced glycation endproduct (AGE) crosslinks. AGE crosslinks abnormally bind proteins together with sugar molecules.

When their orientation is perturbed, such proteins' physical properties are changed and biomechanical function is compromised. AGE crosslinks have been implicated in several age-related pathologies, including atherosclerosis, blindness, hearing loss, type 2 diabetes, and heart disease.

Location and function of some susceptible proteins:

Artery wall: provide elasticity;
Lens of the eye: provide transparency;
Ligaments: provide tensile strength;
Skin: provide elasticity.

By stiffening proteins in arteries, crosslinks cause high blood pressure, increasing wear on the heart. In the eye lens, clumping of proteins changes protein orientation, thus inhibiting lens transparency. In the skin they cause wrinkles.

As with other objects of SENS study, protein crosslinks

are normally benign;
accumulate with age; and,
can become self-reinforcing beyond a threshold.

Unlike intracellular proteins, extracellular proteins don't turn over (or at best only very slowly), making them succeptible to lifetime crosslink accumulation.

That such proteins aren't quickly rebuilt and are exterior to the cell, they must be treated differently from malfunctioning proteins within the cell. Without mechanisms available for either destroying or rebuilding such proteins, as in the case of lysosomal enhancement, we want instead to restore the protein's function -- by severing the crosslinks if possible.

Reinforcing Loop

AGE crosslinks can create self-sustaining loops of crosslink production and resulting damage, so that initially benign levels that evolution would not select against become much more consequential later in life. Crosslinks can even impair the very mechanisms that normally eliminate them.

An example of a reinforcing loop is the case of type 2 diabetes. Crosslinks damage pancreatic beta cells, which produce insulin. Without sufficient insulin levels, blood sugar concentration rises. The higher sugar concentration outside of cells increases the rate of creation of abnormal linking of proteins with sugar. Beta cells thus experience more crosslinking and the cycle renews itself.

Proposed Solution

The proposed solution is to sever these links. Fortunately, the chemistry of such links is unusual in the human body, reducing the risk of AGE breakers severing proteins or other molecules that the body makes on purpose.

More can be read about progress in finding such solvents here.