Age is the number one factor associated with the reduced function of multiple organ systems of almost every known organism. Attempts to efficiently and maximally extend lifespan would, therefore, require a systemic reduction to the rate of aging and improvement to the function of tissue in multiple organ systems. Research published in Aging Cell provides evidence that a single short interval of cellular reprogramming provides a robust and lasting systemic improvement to both the rate of aging and the function in numerous tissues, resulting in an extended lifespan.
Yamanaka Factors and Lifespan Extension
In 2007, Nobel Prize-winning biologist Shinya Yamanaka pioneered research developing a means to reprogram mature, differentiated cells back to stem cells. Forced expression of four proteins, known as Yamanaka factors, is capable of inducing a sort of “cellular amnesia”, resulting in a reversion to their original and more versatile or pluripotent state. Although induced pluripotency is capable of rejuvenating effects, the chronic long-term expression of these factors has been problematic in whole organisms, ultimately leading to cancer and premature death. However, as we reported earlier this year, periodic expression of Yamanaka factors over the lifetime of an organism was capable of reducing the rate of aging in a limited number of tissue systems in mice, and of altering a variety of physiological factors such that they were similar to those of younger animals, while avoiding carcinogenesis and premature death, demonstrating an approach increasing both health and longevity.
Furthermore, the recent work by Q. Alle et al, has shown that utilizing the same periodic approach—over a short period (2.5 weeks), as opposed to the continuous lifelong regime—is sufficient to extend the lifespan of progeroid mice. These mice carry a genetic mutation resulting in a phenotype resembling advanced aging with concomitant degradation of multiple organ systems and severely shortened lifespans, making them ideal models for lifespan-extending interventional studies. In addition to the increased lifespan, tissues from multiple organ systems of mice subjected to a single transient expression period appear to be younger than untreated animals of the same chronological age.
Body Composition and Tissue Preservation
Advanced aging is commonly associated with significant muscle loss known as sarcopenia. Preservation of lean body mass is highly correlated with increases in both healthspan and lifespan. Strikingly, the individual short treatment early in life provides lasting maintenance of lean body mass, antagonizing muscle loss, as well as preventing the increased adiposity commonly associated with advancing age. Following this observed preservation of muscle, treated mice also demonstrated lasting improvement in muscular strength and endurance.
Similar to muscle loss, osteoporosis leads to a significant loss in bone density and is also highly correlated to age. Muscle and bone atrophy are critical factors driving the increased frailty associated with advanced age. Transient early treatment conserved bone volume and thickness, and also maintained the quality of cartilaginous tissues. In addition to contributing to a reduction in frailty through skeletal muscular preservation, various organ systems demonstrated similar improvements: skin, lung, kidney, and spleen all showed improved structural integrity and amelioration of age-related deterioration.
Gene expression can be regulated in a variety of ways, one of which is through modifications to the chromatin structures that DNA is spooled around—a process known as methylation. These methylated sites are collectively referred to as epigenetic marks, and they add a layer of control to gene expression. Epigenetic drift, a loss of fidelity in the pattern of epigenetic marks, is highly correlated with biological age and is thought to be a mechanistic regulator of the aging phenotype. Interrogation of this epigenetic pattern can be used to determine the efficacy of an intervention’s ability to modulate rates of aging.
In this study, brief cellular reprogramming early in life results in a partial reduction of epigenetic drift and preservation of methylation patterns similar to those observed in younger tissues. Interestingly, the patterns of methylation that remain conserved with age are at sites with proximal genes involved in pathways known to alleviate age-related degradation.
Yamanaka factors offer a potentially potent method of promoting longevity and sustaining health. Due to the nature of these interventions and their application being limited to genetically modified laboratory animals, translation to a clinical application will take substantial effort. Importantly, studies such as these demonstrate both the efficacy and safety necessary to justify further pursuits.