Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis.
Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells.
Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.
EDITOR’S NOTE: brief exposure to Yamakana factors (proteins that are used to convert cells to stem cells) somehow reversed many of the epigenetic changes (errors) that accumulate with age, making ‘old’ cells ‘young’ again.
A key question in biology is to understand why and how we age. Alongside this, the unprecedented gain in the average lifespan in humans, since the mid-twentieth century, has dramatically increased both the number of older people and their proportion in the population. This demographic phenomenon is changing our societal make-up, from only ~130 million being 65 years or older (~5% of the world population) in 1950, to a predicted ~1.6 billion people (~17%) by 2050.
However, the success in reducing mortality has not been matched with a reduction in chronic disease. This leads to the undesirable outcome of many years of this prolonged lifespan being spent in ill health, with an associated massive health care burden. Increasing the productivity and reducing the disease affliction in these extended years would be clearly beneficial for both the individual and society.
This aim of maximizing the “healthspan” makes obtaining accurate measures of aging-related pathology essential, to gauge its speed, decipher the changes that occur, and potentially unlock how aging acts as a disease risk factor. There is considerable population variation in the rate at which people visibly age as well as become impaired by age-related frailty and disease. Measurement of this relative “biological” aging may allow pre-emptive targeted health-promoting interventions, perhaps in a personalized and disease-specific fashion. It would also aid in testing interventions that attempt to modulate the aging process.
The cellular and molecular hallmarks of aging include changes associated with cell senescence, dysregulated nutrient sensing, and stem cell exhaustion, among others. Therefore, many biological measures, such as p16ink4a tissue levels, circulating CRP, creatinine, and fasting glucose, as well as telomere length all correlate with aging.
In this decade, we have discovered the remarkable power of epigenetic changes to estimate an individual’s age. Epigenetics encapsulates the chemical modifications and packaging of the genome that influence or indicate its activity, with strict definitions requiring inheritance through mitotic cell division. Observations of age impacting on this mechanism have been reported for more than 50 years and suggested a role in age-related disease.
However, the association between epigenetic modifications and age became most starkly apparent with the arrival of the first high-throughput arrays measuring DNA methylation. These high-resolution data enabled the construction of extremely accurate age estimators, termed “Epigenetic” or “DNA methylation clocks”.
FULL TEXT: BMC Genome Biology