Mice are an ever-present presence at Harvard. They scurry across the halls, chew on wood and plastic objects, and pose electrical safety threats by chewing through wires that carry heat.
But they also teach students about appreciating nature and being resilient when life presents unexpected obstacles, potentially helping us live longer and healthier lives.
Epigenetics
Researchers 13 years in the making have made an astounding breakthrough that could alter aging: They reversed genetic changes that cause age-related genetic deterioration in mice using an epigenetics tool that allowed them to manipulate how DNA is organized and regulated; epigenetics allows cells to change which genes activated or deactivated during cell division; these scientists caused these changes through temporary but fast-healing cuts made in their DNA that mimicked daily low-grade breaks brought about by environmental factors that often contribute to mammalian DNA damage undergoing daily, which allowed them to take control of epigenetic regulation via manipulation of how DNA was organized and regulated allowing them to manipulate how genes were activated or deactivated during cell division; epigenetics is another term used when changing how cells activate or deactivated within cells by making cuts which caused disruption or deactivation by using cuts which mimicking daily low grade breaks which mammalian DNA undergoes as it heals, creating temporary fast healing cuts similar to what mammalian DNA is exposed to as it experiences by environmental factors causing everyday breaks caused by environmental exposure causing daily breaks caused by environmental exposures caused by environmental exposures or breaks occurring within cells by way of manipulation of regulation through regulation via epigenetic regulation changes which affect how genes activate/deactivated/deactivation/deactivation within cells that alter how activate/deactivation/deactivation/activation or deactivation/deactivation/deactivation/deactivation/deactivation/deactivation/regulation changes can change how genes activate/deactivation/deactivation/ reorganization/reorganization or regulate changes by cell interactions or regulation changes within cells induced/ activ/ reorganization/change reorganization/reorganization/re reorganization/activ/activate within cells activate/ activate/deactivation within cells activ/activated/ or activate or activ/ or activ/ or deactivated activate//activate or deactivated/deactivation within cells activate/activated/ deactivation/activation within cells, such as activate or deactiv/activ/deactivation changes within cells v/activations v/activ//activ/ or deactiv/ activ/ deactivations, genes/ activate/de activ/de activ//activ/de activ// deactivations changes may change how cells activate/ or deactivation or cells change (this process called epigenetic changes changes affect genes within cells/ changes or activate/de activ/ or de activ/ de activ/ or changes are activated within cells, changes can change/activations within cells/ activate/ activate// activ// activ//activ/de activ// activ/ deactiv or activate/ deactiv// de activ or de activ/ deactivate or deactiv/ activate or deactiv/ deactiv//activ/ de activ/de activ//de activ// deactiv/ deactiv/de activate/ activate/ or deactiv// or activ/ deactivations within cells etc causing changes through genes which change how activate/ deactiv// etc). scientists created temporary fast-healfre/ activate cells by alteration changes occurring every day due to/or or deactivations by either activate/or/ etc/ change within cells/ etc… or activation within cells when making adjustments changes either way ( or/de/ ). changes caused by either activ/ or//etc cellularization or activate/etc).
When these DNA changes take place, they trigger a chain of reactions which ultimately result in cell death and premature aging. One such reaction involves the degradation of SIRT1, an important protein responsible for keeping genes active by attaching methyl groups. SIRT1 degradation was found to be one of the major contributors to rapid aging seen in ICE mice.
ICE mice appeared and behaved older than mice not receiving treatment, but the team was able to reverse these signs of aging by giving gene therapy that enabled their DNA to lose any methyl groups that prevented genes from activating properly and thus reversed these aging effects. As a result, younger-looking and behaving mice emerged, as well as an ability to grow new blood vessels.
Replicating this experiment on humans will be more challenging, but researchers believe they have a good plan on how to approach it. They will need to raise levels of telomerase which normally shuts off as part of an evolutionary compromise to prevent cancer cells from expanding too quickly, as well as activate DNA repair systems that typically shut off in adults. DePinho remains confident his team are on the right path toward creating an anti-ageing therapy; they plan to test whether raising telomerase levels can extend mice lifespans through slowing cell division rates – if successful this could possibly extend human lives too!
Yamanaka Genes
Shinya Yamanaka made biological history over a decade ago when he discovered how to convert mature skin tissue cells, using four genes, into embryonic stem cells. His work revolutionized scientific research by forgoing human embryos while creating cell types implicated in diseases like heart disease, Alzheimer’s and diabetes. Furthermore, these induced pluripotent stem cells (iPSCs) can serve as models for these conditions while testing new medications against them in Petri dishes.
Although Yamanaka’s method was revolutionary, it also contained certain drawbacks. Gene switches used to induce pluripotency could trigger cancerous cell growth as well as unpredictable results in laboratory experiments due to differences between embryonic stem cells and iPSCs.
Sinclair’s team have modified Yamanaka’s recipe in order to be more precise. By injecting an innocent virus with four Yamanaka genes in sequence, they have managed to precisely target certain cells within mice and cause them to renew themselves by activating the telomerase gene that protects chromosome ends – this results in shorter chromosomes being repaired themselves, leading to more youthful looking cells overall.
Researchers used their method to demonstrate its success by rejuvenating cells derived from genetically engineered mice lacking an enzyme called telomerase, without which cell division leads to shorter telomeres – leading to cell senescence – which ultimately leads to premature cellular aging. They discovered that by activating their telomerase gene they could extend artificially aged mouse lives by 109%!
While this study is promising, it remains too soon to tell whether its approach will work in humans and there remain questions as to how accurate their ICE model of natural aging is. “Their indirect approach of inducing epigenetic changes by creating dramatic DNA breaks makes it hard to know if their model accurately represents natural aging,” according to Wolf Reik of Altos Cambridge Institute of Science (opened by rejuvenation company Altos Labs last year) while direct genetic approaches used by Harvard team like reactivating telomerase are better ways of making natural aging more like.
Reactivation of Telomerase
With each cell division, telomeres — protective caps at the end of chromosomes that protect chromosomes against damage — become shorter. Once they reach critical length, cells enter a state known as senescence – and may ultimately enter an inactive state known as senescence. Reactivating telomerase may be key to prolonging human lifespan and treating age-related illnesses like cardiovascular disease, diabetes, cancer and Alzheimer’s.
As part of its defense against shortening telomeres, cells produce an enzyme known as telomerase that adds DNA repeats each time it divides. Unfortunately, this enzyme becomes less and less active over time and eventually inactive after multiple rounds of divisions. Researchers have identified several genes which activate telomerase to counteract this degradation, including SIRT1 which has been found induced by red wine and certain nuts such as walnuts.
Scientists from Harvard Medical School believe they may have come one step closer to discovering the Fountain of Youth through rejuvenating old mice. A study published in Cell shows how these scientists were able to reverse aging by restoring cells’ communication between cells.
This team of scientists utilized viral vectors to introduce Yamanaka factors (OCT4, SOX2, KLF4 and hTERT) into mouse embryonic stem cells. After transplantation into older mice, their transformed cells reversed many aspects of aging such as tissue function restoration and extended lifespan.
Though their experiment was successful, the team remains uncertain whether similar outcomes can be obtained with mature human cells. Reactivating telomerase in these more fragile human cells often proves more challenging; additionally, their genome is much larger and complex than that of mice.
Sinclair and his group remain hopeful that they can extend the lifespan of human cells using resveratrol and Yamanaka genes to induce cellular reprogramming, with hopes that such research may one day result in the creation of an anti-ageing pill that effectively treats multiple age-related conditions.
Rejuvenation
Researchers from Harvard Medical School and Brigham and Women’s Hospital may have come a step closer to rejuvenating aged mice, yet their discovery could come too late for millions suffering from age-related illnesses.
Researchers discovered they could turn back time using epigenetics – reactivating genes involved in rejuvenation using chemical cocktails – using this strategy to turn back time in mice by switching off genes involved with degradation while activating rejuvenative genes. Published today in Cell, their study indicates how chemical cocktails can reverse the aging process by turning off those involved with degradation while activating rejuvenative genes.
This results validate what is known as the information theory of aging: our cells lose epigenetic markers that degrade as they go through cell divisions. To test this idea, scientists in David Sinclair’s laboratory caused several dramatic DNA breaks to mice which cause repair mechanisms to kick in more quickly than usual, thus altering methylation patterns (an epigenetic marker used to tell age), thus changing methylation profiles of young and old mice allowing researchers to identify which chemicals were responsible for turning back time.
Sinclair and her team reprogrammed mouse skin cells into embryonic stem cells, the versatile precursors for all body tissues and organs. These iPS cells were then used to treat specific forms of damaged tissue – first retinal ganglion cells in the eyes which control vision – by switching on specific genes; these reprogrammed iPS cells healed damage caused by retinal ganglion cells by turning back time; this restored vision to that seen when these mice were young again. Brain, muscle and kidney cells were then also restored back into youth!
Scientists will now turn their focus toward testing GDF-11 on humans, with clinical trials for humans scheduled to commence within four or five years. Aubrey de Grey of SENS Foundation fame, who spearheads rejuvenation therapies such as GDF-11 delivery evenly to all cells within an individual, praises this work but warns that there remains an equally difficult challenge: getting all cells using it at the same time.
