Recent Breakthroughs in Research Give Hope in the Quest to Cure Aging
Potential Treatments for Aging are in the Works
Recent research suggests that aging is treatable and potentially reversible. The identification of the nine inter-related hallmarks of aging in the 2013 review paper “The Hallmarks of Aging” in the journal Cell, brought the notion that aging could be addressed therapeutically into the mainstream and spawned a flurry of research into the aging process. At the time of this writing, the 2013 paper, “The Hallmarks of Aging,” has been cited over six thousand times. Additionally, the advent of new technologies for genetic programming, such as CRISPR-Cas9 in 2013 [10], discoveries in the field of stem cells, most notably the discovery of Yamanaka factors, to generate Induced Pluripotent Stem Cells (IPSCs) from somatic cells by Shinya Yamanaka in 2006 [1], and technological advancements in the field of proteomics such as more precise and efficient microscopy, histology, and mass spectrometry [2], have given scientists the tools necessary to attempt to target the hallmarks of aging and repair them. Advances such as these have led to several anti-aging breakthroughs in recent years, with a central theme being that targeting just one hallmark of aging usually confers benefits to multiple other hallmarks.
Recent Successes in Research:
· Using Yamanaka Factors to Reprogram Cells to a Younger State: One of the greatest breakthroughs involved the use of Yamanaka factors, four master genes, Oct4, Sox2, Klf4, and c-Myc (OSKM), which can be induced and expressed in somatic cells to create induced pluripotent stem cells (iPSCs). IPSCs are very similar to embryonic stem cells, in that they do not have a cellular identity and have the capability of differentiating into any type of cell (pluripotency). In 2016, researchers at the Salk Institute demonstrated that “partial reprogramming” using a short-term cyclic Yamanaka factor protocol to briefly activate and then deactivate Yamanaka factors returned prematurely-aged cells and tissues to an epigenetically and physiologically younger state, without turning the cells all the way into stem cells. When this was performed in vivo (live specimen) in prematurely aged (progeroid) mice, the researchers found that it rejuvenated the mice, extending lifespan by 25% without leading to loss of cellular identity or tumor formation. This translated to improvement in common aging phenotypes in the skin, spleen, kidneys, muscle, and stomach tissues. Intriguingly, this research is especially significant because it showed that multiple aging hallmarks — epigenetic alterations, cellular senescence, and stem-cell depletion — were improved with this one therapy [3].
The work at Salk has opened the door to the future possibility of using Yamanaka factors to epigenetically reprogram humans to a younger state. While this has exciting implications for extending life and health, more research is needed. The focus currently is on using three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (OSK) to restore vision by reprogramming aged or damaged eyes to a younger state, and this has now been done successfully in old mice and mice with glaucoma [4]. The next step will be testing the Yamanaka factors (OSK) on the entire body of aged mice in vivo, and if successful, moving to clinical trials in humans.
· NAD+ supplementation: NAD+ is a molecule which is essential for cellular respiration, yet levels of NAD+ decline with age, apparently because NAD+ is actively destroyed by the enzyme CD38 [5]. Addressing the issue of CD38 destroying NAD+ requires further research, so instead, boosting NAD+ levels is currently being investigated as a treatment. NAD+ precursor supplements are being marketed as anti-aging therapies, although research in mice has demonstrated only modest health and lifespan improvements with these supplements so far. Nevertheless, NAD+ precursor supplements, such as Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR) have been shown to increase NAD+ levels in the tissues of aged mice [6], and higher NAD+ levels are beneficial in light of several of the hallmarks of aging. Higher NAD+ levels stabilize telomeres by activating sirtuins [7], and improve mitochondrial and stem cell function [8]. These cellular changes are reflected in increased performance of aged mice during endurance exercise and better vascular functioning and vascular regeneration [9]. A project to elucidate the long-term effects of NMN supplementation on mice is being led by Dr. David Sinclair, a professor at Harvard whose specialty is aging and genetics, and is set to conclude in late 2020.
· Thymus Regeneration: The thymus is an organ of the immune system, located between the lungs, and it is responsible for producing T-cells, which are an integral part of the adaptive immune system. As we age, in a process called thymic involution, the thymus gland shrinks and is eventually replaced entirely by fat at the age of 65. Immunosenescence is an effect of thymic involution, and hormonal therapies to regenerate the thymus have had promising beneficial results in terms of improved immune functioning in the elderly. A thymus regeneration study, published in 2019, was conducted at UCLA by Steve Horvath, a Professor, geneticist, and bio-statistician, who developed an epigenetic clock (Horvath clock) which can be used to determine biological age, as opposed to chronological age. The study, Thymus Regeneration, Immunorestoration, and Insulin Mitigation (TRIIM), involved 51–65 year old men who were administered a drug cocktail of 3 drugs: recombinant human growth hormone (rHGH) to restore HGH levels, metformin, a known anti-aging drug that functions as a dietary restriction and exercise mimetic, and dehydroepiandrosterone (DHEA), a synthetic version of the natural hormone necessary for production of testosterone and estrogen, levels of which drop with age. After 1 year of TRIIM, epigenetic age was reversed by 2.5 years on average, and observed effects included thymus regrowth, decreases in inflammation, and improved immune health [10].
· Hypothalamus stem cell rejuvenation: In 2017, researchers discovered that the hypothalamus, a region of the brain responsible for the release of hormones, appears to regulate the speed of aging via the release of exosomal microRNAs, which diminish with age due to depletion of hypothalamic stem cells. When stem cells were injected into the hypothalamus in mice, aging was slowed and lifespan was increased by about 10% [11].
· Senolytics: Senolytics, small molecules which aid the removal of senescent cells, are a proposed treatment for the accumulation of senescent cells with age. Senescent cells are dysfunctional, and are one of the causes of inflammaging, the increased smoldering background inflammation with age, which is linked to decreased immune functioning, increased cancer-risk, and various other age-related diseases such as frailty, atherosclerosis and Alzheimer’s [12]. A study published in 2018 in the journal Nature found that when the senolytics Dasatinib plus Quercetin (D+Q) were administered to aged mice, there was a decrease in inflammation, improvement in physical activity, and an increase in life-span by 36% [13]. Senolytic therapies such as D+Q have now moved into clinical trials for a variety of diseases, and preliminary results show decreased numbers of senescent cells in humans, and that senolytics appear have minimal side-effects [14].
Conclusion
This paper covers several of the major breakthroughs in aging research in recent years, and each proves that aging is a modifiable process that can be adjusted to confer health benefits and extend lifespan. With more research and clinical trials, we could soon see these potential therapies in actual practice by medical professionals. More funding is definitely needed to accelerate such research.
Interested in how much funding is available for aging research, where it comes from, and how we can advocate for more? Read my final article in this series, “Aging Research; Where is the funding?”
Missed my first two articles, find them here: “Where is the ‘Operation Warp Speed’ for Aging?” and here: “What Causes Aging? How Much Have we Learned in Recent Years?”
References:
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