Lifeboat Foundation: Safeguarding Humanity
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Category: life extension – Page 166

Scientists at Harvard Medical School have investigated why we age, and identified a possible way to reverse it. In tests in mice, the team showed that epigenetic “software glitches” drive the symptoms of aging – and a system reboot can reverse them, potentially extending lifespan.

Our genome contains our complete DNA blueprint, which is found in every single cell of our bodies. But it’s not the whole picture – an extra layer of information, known as the epigenome, sits above that and controls which genes are switched on and off in different types of cells. It’s as though every cell in our body is working from the same operating manual (the genome), but the epigenome is like a table of contents that directs different cells to different chapters (genes). After all, lung cells need very different instructions to heart cells.

Environmental and lifestyle factors like diet, exercise and even childhood experiences could change epigenetic expression over our lifetimes. Epigenetic changes have been linked to the rate of biological aging, but whether they drove the symptoms of aging or were a symptom themselves remained unclear.

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Chromatin structures and transcriptional networks are known to specify cell identity during development which directs cells into metaphorical valleys in the Waddington landscape. Cells must retain their identity through the preservation of epigenetic information and a state of low Shannon entropy for the maintenance of optimal function. Yeast studies in the 1990s have reported that a loss of epigenetic information compared to genetics can cause aging. Few other studies also confirmed that epigenetic changes are not just a biomarker but a cause of aging in yeasts.

Epigenetic changes associated with aging include changes in DNA methylation (DNAme) patterns, H3K27me3, H3K9me3, and H3K9me3. Many epigenetic changes have been observed to follow a specific pattern. However, the reason for changes in the mammalian epigenome is not yet known. A few clues can be obtained from yeast, where DSB is a significant factor whose repair requires epigenetic regulators Esa1, Gcn5, Rpd3, Hst1, and Sir2. As per the ‘‘RCM’’ hypothesis and ‘Information Theory of Aging’’, aging in eukaryotes occurs due to the loss of epigenetic information and transcriptional networks in response to cellular damage such as a crash injury or a DSB.

A new study in the journal Cell aimed to determine whether epigenetic changes are a cause of mammalian aging.

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The maximum lifespan varies more than 100-fold in mammals. This experiment of nature may uncover of the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and maximum lifespan, we carried out a comparative transcriptomics analysis of liver, kidney, and brain tissues of 106 mammalian species. We found that expression is largely conserved and very limited genes exhibit common expression patterns with longevity in all the three organs analyzed. However, many pathways, e.g., “Insulin signaling pathway”, and “FoxO signaling pathway”, show accumulated correlations with maximum lifespan across mammals. Analyses of selection features further reveal that methionine restriction related genes whose expressions associated with longevity, are under strong selection in long-lived mammals, suggesting that a common approach could be utilized by natural selection and artificial intervention to control lifespan. These results suggest that natural lifespan regulation via gene expression is likely to be driven through polygenic model and indirect selection.

The authors have declared no competing interest.

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Why do cells, and by extension humans, age? The answer may have a lot to do with mitochondria, the organelles that supply cells with energy. Though that idea is not new, direct evidence in human cells had been lacking. Until now.

In a study published Jan. 12 in Communications Biology, a team led by Columbia University researchers has discovered that human cells with impaired mitochondria respond by kicking into higher gear and expending more energy. While this adaptation—called hypermetabolism—enhances the cells’ short-term survival, it comes at a high cost: a dramatic increase in the rate at which the cells age.

“The findings were made in cells from patients with rare mitochondrial diseases, yet they may also have relevance for other conditions that affect mitochondria, including neurodegenerative diseases, inflammatory conditions, and infections,” says principal investigator Martin Picard, PhD, associate professor of behavioral medicine (in psychiatry and neurology) at Columbia University Vagelos College of Physicians and Surgeons.

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This process can occur endlessly and allows the jellyfish to escape death.

Achieving immortality has driven human beings throughout much of their history. Many peculiar legends and fables have been told about the search for the elixirs of life. Medieval alchemists worked tirelessly to find the formula for the philosopher’s stone, which granted rejuvenating powers. Another well-known story is the travels of Juan Ponce de León, who searched for the mysterious fountain of youth while conquering the New World.

But to this day, no one has discovered the keys to eternal life. However, there is one exception — a creature no more than four millimeters in size, Turritopsis dohrnii.

Biological immortality, within reach of a jellyfish

Unlike most living organisms, Turritopsis dohrnii can rejuvenate and have biological immortality. This challenges our perception of aging, but how does it do so?

Let’s start by understanding the generic life cycle of a “mortal jellyfish”. It reproduces sexually: the male’s sperm fertilizes the female’s eggs, and the zygote is formed. The zygote grows as a larva and drifts until it attaches itself to the seabed. Once settled, it grows into a polyp, and when ready, it reproduces asexually. To do this, it releases tiny jellyfish from its own body, which then grow to the adult stage and reproduces, before dying.

Continue reading “Immortal jellyfish: Scientists are deciphering genes to learn secrets” | >

The rebooting came in the form of a gene therapy involving three genes that instruct cells to reprogram themselves—in the case of the mice, the instructions guided the cells to restart the epigenetic changes that defined their identity as, for example, kidney and skin cells, two cell types that are prone to the effects of aging. These genes came from the suite of so-called Yamanaka stem cells factors—a set of four genes that Nobel scientist Shinya Yamanaka in 2006 discovered can turn back the clock on adult cells to their embryonic, stem cell state so they can start their development, or differentiation process, all over again. Sinclair didn’t want to completely erase the cells’ epigenetic history, just reboot it enough to reset the epigenetic instructions. Using three of the four factors turned back the clock about 57%, enough to make the mice youthful again.

“We’re not making stem cells, but turning back the clock so they can regain their identity,” says Sinclair. “I’ve been really surprised by how universally it works. We haven’t found a cell type yet that we can’t age forward and backward.”

Rejuvenating cells in mice is one thing, but will the process work in humans? That’s Sinclair’s next step, and his team is already testing the system in non-human primates. The researchers are attaching a biological switch that would allow them to turn the clock on and off by tying the activation of the reprogramming genes to an antibiotic, doxycycline. Giving the animals doxycycline would start reversing the clock, and stopping the drug would halt the process. Sinclair is currently lab-testing the system with human neurons, skin, and fibroblast cells, which contribute to connective tissue.

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