A Sensible Consideration of the State of the Art in the Treatment of Aging as a Medical Condition
It used to be the case that one could write up a summary of where the research community stood on the treatment of aging as a medical condition (which was varying shades of "not that far along towards practical applications, but definitely promising if they get their act together") and then not have to update it all that much for years. Research is slow and uncertain, for one, and secondly there was, for decades, a strong cultural prejudice in the scientific community against trying to apply what was learned about aging to the treatment of aging. Little progress was made as a result.
Matters are proceeding much more rapidly nowadays. The prejudice is vanished, that change the result of a great deal of hard work by advocates, philanthropists, and researchers. Many of the potential approaches to treating aging as a medical condition hypothesized in past decades have either become practical, such as the selective destruction of senescent cells, or are within a few years of making the leap from laboratory to clinical development. The state of the art in the treatment of aging in 2010 already looks quaintly dated.
More activity in research and development means more attention given to the subject, faster progress, a greater need for summaries and explanations that are more up to date. It is good to see more people trying their hand at learning the state of the art and explaining it to others. One can always disagree with some of the selections when it comes to picking the most important lines of work, but the underpinnings of the article I'll point out today are good. It is well worth sharing with anyone you might think interested in the field.
Today, there are over 130 longevity biotechnology companies and over 50 anti-aging drugs in clinical trials in humans. The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans. Whether we live to see anti-aging therapies to keep us alive indefinitely (i.e. whether we make it to longevity escape velocity) depends on how much traction and funding the field gets in coming decades.
Aging is essentially damage that accumulates over time, which exponentially increases the risk of the diseases that kill most people. This 'damage' associated with aging comes in essentially nine forms, known as the hallmarks of aging. These forms of cellular damage drive the increased risk of disease, frailty, cognitive decline as well as observable signs of aging such as grey hair and wrinkles. The 'damage' (hallmarks of aging) occurs as a by-product of normal metabolism - the biochemical reactions that keep us alive. More and more damage accumulates and eventually leads to pathology, i.e. disease. When we talk about anti-aging we are talking about fixing the damage using an engineering approach before it accumulates to a dangerous level at which diseases emerge.
Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging due to the Taueber paradox and the highly co-morbid nature of age-related diseases. Even if a person survives one age-related disease such as cancer, another (e.g. diabetes, cardiovascular disease) will kill them if aging is not solved. This accounts for the much smaller increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years). The difference between anti-aging and current medicine is the former prevents illness by targeting the hallmarks of aging, whereas the latter intervenes once a disease has emerged. If we compare current medical interventions associated with geriatrics with anti-aging - the former extends unhealthy lifespan, whereas only the latter extends healthy lifespan.
The past five years of research have demonstrated several anti-aging strategies as particularly promising. Heterochronic parabiosis is putting young blood into old mice, to make the old mice biologically younger. This is achieved in the lab by connecting the circulatory systems of young mice and old mice. Recently, a group of Russian biohackers recently performed the first plasma dilution experiments in humans. In a research context, the safety and effectiveness of apheresis is being tested in a clinical trial in humans by the company Alkahest.
Dietary restriction has been shown to extend healthy lifespan across several species. Drugs that mimic the metabolic effects of dietary restriction also have beneficial effects on lifespan. Nutrient-sensing biochemical pathways (such as IGF-1, mTOR, and AMPK) play a key role in these effects. Metformin is a drug that is FDA-approved for diabetes that extends healthy lifespan in mice by inhibiting mTOR and activating autophagy. Metformin is currently being tested in a large clinical trial in humans to test its anti-aging properties. Another promising drug that manipulates metabolism is rapamycin, an FDA-approved immunosuppressant that extends healthy lifespan in mice and similarly acts to inhibit mTOR. Rapamycin is currently in a clinical trial in humans to test its anti-aging properties.
Senescent cells are a kind of 'zombie'-like cell that accumulate with age. They are death-resistant cells that secrete proinflammatory factors associated with a range of age-related diseases. There are various strategies being explored to kill or reprogram senescent cells, including senolytics. Senolytics are drugs that kill senescent cells to improve physical function and healthy lifespan. When administered to older mice, senolytics have been shown to reverse many aspects of aging such as cataracts and arthritis. Killing senescent cells with senolytics extends the median healthy lifespan in mice. Several senolytics, such as the combination of dasatinib and quercetin, and fisetin are in clinical trials in humans today.
Cellular reprogramming is the conversion of terminally differentiated cells (old cells) into induced pluripotent stem cells (iPSCs) ('young' cells). Cells can be re-programmed to a youthful state using a cocktail of factors known as Yamanaka factors. iIPSCs have essentially unlimited regenerative capacity and carry the promise for tissue replacement to counter age-related decline. Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer. An impressive example of cellular reprogramming was the restoration of vision in blind mice with a severed optic nerve using three of the four Yamanaka factors.