Chapter 170
Changing Aging — 7
Further spotlighting the prominence of epigenetics with aging, Belmonte used CRISPR genome editing that targeted histone marks, instead of standard genome editing directed to DNA, achieving improved outcomes in mouse models of type 1 diabetes, muscular dystrophy, and acute kidney injury. Many subsequent studies from Belmonte and independent labs have replicated the potential for rejuvenation via epigenetic reprogramming, including animal organ studies of the heart, liver, eye, nerve fibers, pancreas, skin, and skeletal muscle. There is also a way to sidestep the Yamanaka factors with chemical reprogramming. Back in 2013, Hongkui Deng and his group in Beijing, China, discovered an alternative way of reprogramming to achieve pluripotent stem cells using a cocktail of small molecules. More recently, like Belmonte’s team, they have adopted this small molecule epigenetic reprogramming to rejuvenate cells. Although there has been less work (in vivo) in experimental models, this is a distinctly different and efficient way of reprogramming and may prove to be a useful strategy. It avoids the problems of viruses and gene therapy and is potentially considerably cheaper.
Protein Housekeeping (Proteostasis) and Cellular Garbage Removal
The loss of proteostasis with aging can lead to misfolded or aggregated proteins, as commonly seen with cataract formation, and as an underpinning of neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. The cell’s ubiquitin pathway helps package the proteins that need to be discarded through the proteasome waste disposal system. Garbage removal is one of the cells’ most vital and elaborate functions, not just for getting rid of misfolded proteins or ones that were improperly made. Inside the cell, the waste disposal process depends substantially on an organelle called the lysosome, which collects dud proteins and mitochondria into a kind of garbage bin. In the cell cytoplasm, there are autophagosomes, which transport these garbage bins, functioning as garbage trucks ridding the cell of waste products. This cleaning process, called autophagy, gets less efficient with age. Eventually the accumulation of waste and the bursting of lysosomes and mitochondria induce significant inflammation and oxidative damage to cells and tissue. Many compounds that activate autophagy have been linked to longer lifespan in animal models, such as metformin or rapamycin. Caloric restriction and physical activity also help promote cellular house cleaning.
Nutrient Sensing and Mitochondrial Dysfunction
Here’s where growth hormone, glucose, insulin, IGF1, IGF-1R (insulin growth factor-1 receptor), amino acids, and the entire nutrient network that regulates so many cellular functions come into play. It feeds the powerhouses of the cell, the mitochondria. As I reviewed in chapter 3, there’s been intensive study of caloric restriction in animal models, which in rodents, yeast, and fruit flies support lifespan extension with marked reduction of about 40 percent of daily caloric intake. However, the evidence in nonhuman primates is mixed, with lack of replication of lifespan extension. In humans, function of the thymus, a key regulator of our immune system, was improved with a 14 percent caloric restriction diet (considerably easier than the restriction levels in the animal model studies) for two years, along with various salutary metrics of reduced inflammation and improved mitochondrial function. Likewise, two years of mild (12%) caloric restriction significantly reduced biological age in more than seventeen hundred participants. In experimental models, various manipulations of the cell’s ability to respond to fuel substrates, such as modulated by growth hormone or IGF-1 inhibition, a ketogenic diet, sirtuin activators, and mechanistic targets of rapamycin (mTOR), have been shown to have functional consequences on mitochondrial function, inflammation, autophagy, and cellular senescence. Mitochondrial-derived vesicles, which transport cargo inside the cells to lysosomes and other organelles, are increasingly recognized for their role in the aging process. It makes sense; if you can’t process nutrients, you aren’t going to be as healthy.