Shared Epigenetics in Methods of Slowing Aging in Mice
The Genome Biology journal recently published a set of open access papers on the epigenetic changes observed in mice subject to a few of the methods known to slow aging in mammals, and you'll find them linked below. In particular the focus is on DNA methylation, an molecular decoration to nuclear DNA that determines the pace at which proteins are produced from the blueprints encoded by specific genes. Changes in the amounts of proteins in circulation inside the cell are the switches and dials of cellular behavior, which in turn feeds back to determine ongoing changes in DNA methylation. It is a complex, dynamic situation.
Some of the thousands of DNA methylation markers that come and go in mammalian cells are reactions to the damage of aging; accumulations of metabolic waste and altered macromolecules. That low-level damage is the same for everyone, and so some part of the changing pattern of DNA methylation that accompanies aging is also the same for everyone. That part of the pattern can thus be used to determine how aged an individual is, how much damage their tissues have sustained, and how likely it is that the accumulated damage will kill them sometime soon. This is, in any case, the hope of researchers working on DNA methylation biomarkers of aging. The data generated to date is quite compelling.
What is the point of all this? The goal is to generate an effective, cheap, accurate biomarker of aging that can be used to quickly assess the performance of proposed rejuvenation therapies. At the present time if researchers selectively eliminate senescent cells from a patient, for example, they can only look at short-term changes, such as how many cells they successfully removed, or whether the patient exhibits immediate benefits in known assays for disease pathology. They cannot currently accomplish a rapid assessment the treatment's outcome on remaining life expectancy and future health. The only way to find out is to wait and see. This makes work on rejuvenation treatments very slow and expensive, as even in mice this requires waiting for years. A robust DNA methylation biomarker of aging, on the other hand, could run immediately before and immediately after a treatment: much faster, and much cheaper. Some teams have already started testing this approach on the presently known methods to slow aging in mice - you might look at a recent Harvard paper that builds upon the observations in the papers linked below, but which is unfortunately not open access.
One interesting point to take away from this is that there remains considerable debate over what is the cart and what is the horse in the matter of aging and alterations in the epigenome. A purist approach to the view of aging as accumulated damage is to see these epigenomic changes such as DNA methylation to be cellular reactions to rising levels of damage, or at least somewhere a fair way downstream of that damage. In these papers you'll see some of the opposite view, that these changes are an important cause of aging - that they are closer to a primary problem than a later downstream change that in and of itself causes further issues. I can't say as I think that is as defensible a viewpoint, but there are many researchers who hold it.
Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging.
Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction, or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.
Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction, and rapamycin.
In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.
Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.
Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.