In an eloquent commencement speech by Steve Jobs to the 2005 graduates of Stanford University, Jobs said the following, ‘No one wants to die. Even people who want to go to heaven don’t want to die to get there. And yet death is the destination we all share. No one has ever escaped it. And that is as it should be because death is very likely the single best invention of life. It is life’s change agent. It clears out the old to make way for the new. Right now the new is you, but someday not too long from now, you will gradually become the old and be cleared away. Sorry to be so dramatic, but it is quite true.’
Dramatic indeed, but Mr. Jobs is not the first to fascinated by death; since ancient times, humans have sought eternal youth. Therefore, it comes as no surprise that with our growing elderly population, there is great interest in the development of technologies and medicines to combat the symptoms of aging.
Alzheimer’s disease (AD) is the most common neurodegenerative disease today with devastating consequences for patients and families alike. Developing treatments for patients with AD and other forms of dementia is a pressing concern for the medical field. The prevailing theory in the field of AD research is that the disease develops as a result of the accumulation of a protein called β-amyloid (Aβ) inside the brain; therefore, most treatments are focused on preventing and clearing the built-up β-amyloid protein.
For example, a recent study examined the usefulness of the drug taxifolin in relieving the Aβ protein load in a disease mouse model. Taxifolin is a drug with anti-oxidative properties, which has been shown to disassemble Aβ aggregates in vitro. Taxifolin’s effectiveness in an animal model prone to cerebral amyloid angiopathy (CAA) was tested and it was found that Taxifolin decreased the amount of smaller Aβ structures, referred to as oligomers, to ¼ the levels seen in animals treated with the vehicle control. Notably, decreases in accumulated Aβ were observed in the area of the brain related to memory, called the hippocampus. When the researchers assessed for clinical improvements they found the CAA mice treated with Taxifolin showed improved cerebral blood flow compared to untreated mice and in fact, their cerebral blood flow had normalized to levels seen in wild-type mice. Spatial learning and memory were tested using the Morris water maze and the researchers showed CAA-mice treated with Taxifolin showed similar competency to wild-type mice while the vehicle-treated controls maintained their poor performance. These results suggest Taxifolin has the ability to decrease the accumulation of toxic misfolded proteins which may lead to a recovery of function. Potentially, with further investigation and validation, this could lead to novel therapeutics for this debilitating disease.
（Image: Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity as well as memory function in a cerebral amyloid angiopathy mouse model）
In an alternate approach, researchers targeted the β-secretase enzyme (BACE) which cleaves the amyloid precursor protein to produce β-amyloid. After 8 weeks of treatment with a BACE inhibitor, transgenic mice showed improved memory function in the water maze test and reduced levels of β-amyloid in the brain.
While these studies look at mouse models aiming to mimic AD pathology, perhaps the best way to delay the progression of the disease is through early intervention prior to neurodegeneration. Currently, researchers and doctors are investigating whether drugs targeting β-amyloid accumulation can be applied when patients exhibit symptoms of the early stage disease, referred to as mild cognitive impairment (MCI).
While the research described above took place in academic institutions, companies, including startups, have also shown interest in the development of medicines and treatment methods for age-related neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease and Friedreich’s ataxia.
Heterocephalus glaber, more commonly known as the naked mole rat, is a unique rodent species. These animals do not develop cancer, and live for nearly 30 years compared to typical mice which live for approximately 1-3 years; as such, they have been a subject of great interest for the research community investigating the processes of aging and longevity.
Scientists now understand these rodents are highly resistant to cancer due to their early expression of p16Ink4a, a protein which inhibits cell proliferation. Humans also carry these cell cycle inhibitors as well as others such as p27Kip, but they are not expressed as early as in the rodent model. Interestingly, research has shown that the removal of stagnant, aged cells expressing p16Ink4a can also be beneficial and extend a mouse’s life.
(Image: Naturally occurring p16Ink4a-positive cells shorten healthy lifespan)
In addition to the work studying aging and anti-aging, researchers have also asked the question, is rejuvenation possible?
An interesting new avenue of research suggests young blood may have rejuvenation properties when inserted in an older animal. Aged mice were injected with blood plasma from younger mice and exhibited improvements in memory. Exposure to young mouse blood was also associated with increases in the density of dendritic spines. Conversely, young mice exposed to older blood deteriorated dramatically and within days showed poorer physical performance and reduced neurogenesis.
（Image: Ageing, neurodegeneration and brain rejuvenation）
It has been suggested that aging throughout the whole body is controlled by the hypothalamus. The number of neural stem cells in the hypothalamus decreases naturally, and this decrease likely accelerates aging. Researchers have shown that by adding supplemental stem cells to the hypothalamus or simply introducing the molecules released from these neural stem cells can delay aging. Therefore, modulation of the stem cell population in the hypothalamus may be another unique method to stave off the aging process.
(Image: Hypothalamic stem cells control aging speed partly through exosomal miRNAs)
While there are many definitions to describe life, perhaps a good summary would be to think of it as an individual or collective molecular machine that is controlled by DNA, which it can then pass on to it’s future descendants. If DNA is information, the brain is can be thought of as the information processing equipment; although, one must consider the fact that the brain also produces information in that it creates memories, and establishes processes for inputs and outputs.
If we think of life as this flowing of information as a result of our brains and DNA, then perhaps as we improve technology this information will become permanent. For instance, the science fiction world has proposed a future where our brains are uploaded into computers. This is a far-off possibility, but it still begs the question: what will be the significance of death if our information or “essence” is permanently preserved. But before our brains can ever be uploaded into computers, there is still much to learn regarding brain function. Thankfully, in Europe there is The Human Brain Project and in the USA the BRAIN Initiative, both of which seek to understand patterns in brain activity and to decode how the brain works. Addressing these questions would be important milestones on the road to achieving “virtual immortality.”