Chapter 172
Changing Aging — 9
How cells talk to one another within tissues and long range is altered by aging, with the exemplar being a phenotype of senescent cells termed SASP, the senescent cells capable of secreting various soluble factors, growth factors, and extracellular matrix–remodeling enzymes. Aged immune cells are not only in close communication with one another but also signaling throughout the body. Inflammation of our gums has been recognized as a risk factor for heart arrhythmias in the form of atrial fibrillation. In an experimental model, stressed mitochondria from microglia cells in the brain were shown to communicate with cells throughout the body to promote repair. Notably, in developing the muscle cell atlas of aging, researchers created “CellChat” to wiretap cell-to-cell interactions that occur through elaborate circuits. They observed that certain interactions doubled with aging, particularly ones that promote the muscle-wasting process through inflammation, dysregulation of growth factors, and excessive deposition of extracellular matrix. This just scratches the surface for the intricate crosstalk occurring between cells that is strongly influenced by the aging process.
Aseries of recent studies indicates that chatter between organs promotes health and in experimental models extends lifespan. Muscle tissue sends out six hundred molecular signals, fat more than one hundred, which are widely interacting with other organs, not just via circulating blood. For example, activating the communication between the hypothalamus and fat tissue enhanced physical activity and improved lifespan in the mouse model. This occurred via the sympathetic nervous system, mediated by fat cell secretion of the signal extracellular nicotinamide phosphoribosyl-transferase. When these extracellular vesicles from young mice are infused into old ones, lifespan is extended. Bone is another important source of chatter, and its osteocalcin signal promotes liver release of insulin and muscle absorption of glucose, and improves cognition. Another example of organ-organ crosstalk comes from the heart, which has a stress memory, leading to epigenetic marks on blood stem cells, setting up recurrence of heart failure and damage to kidney and skeletal muscle in the mouse model. So many of our body-wide interorgan circuits are getting redrawn, providing further clues on how to modulate the aging process in experimental models.
Chronic Inflammation
Inflammaging is the process of systemic inflammation with aging, but it is highly variable from one individual to another as measured by C-reactive protein, interleukin-6, tumor necrosis factor-α (TNF), and latent virus infections. More extensive and durable chronic inflammation has been linked to promoting cancer as well as neurodegenerative, cardiovascular, and metabolic diseases. In the aged mouse model, interleukin-11 (IL-11) inhibition, which works in the interleukin-6 pathway, had a broad effect of improving metabolism and muscle function, blocking tumors, changing white fat to beige fat, and significantly expanding lifespan, adding more support for inflammation as a driver of aging, and as a possible intervention since this drug is already in clinical trials for interstitial lung disease. The potential to combine this with an interleukin-6 blocker, which has suppressed heart disease and cancer in a large randomized trial, is alluring. There is a way to do just that. Much of the inflammation unleashed by the activated NLRP3 inflammasome,I a large protein complex of our innate immune system, can be blocked by small molecules (pills) that inhibit multiple key pro-inflammatory proteins including interleukin-1β and interleukin-6. There are many other potential drivers of untoward inflammation that are not yet unraveled, but the cGAS-STING pathway (comprised of cyclic GMP-AMP synthase [cGAS]), stimulator of interferon genes (STING), in the cell cytoplasm, has been implicated as a major mediator. It is activated by cell damage, such as sensing DNA leak from mitochondria. When this pathway is blocked, age-related inflammation of multiple organs and the brain is reduced.