快猫短视频

IT WAS as if someone had turned back time. Once-faltering paws gripped objects with renewed strength. Hearts and livers regained their youthful vitality. Fuzzy memories sharpened. And according to Steve Horvath鈥檚 experiments, the . 鈥淚 was stunned,鈥� he says.

Horvath, an anti-ageing researcher at the University of Los Angeles, California, and his colleagues saw these startling effects in 2020 after injecting old rats with blood extract from younger rodents. And they are not alone. A growing number of labs are reporting findings that indicate we might have been thinking about ageing the wrong way.

Rather than the result of the accumulation of wear and tear as time ticks by, ageing could be driven by the forces that build our bodies in the uterus and maintain them after we are born. In youth, they help us, but a failure to switch them off brings the deterioration of old age. This new view offers a deeper understanding of what ageing actually is and the possibility of slowing or even partly reversing it.

While the processes that drive ageing are a matter of debate, biogerontologists do agree on one thing 鈥� what it looks like: the progressive decline in physical function that most creatures experience with the passage of time. They have catalogued the cellular changes accompanying this decline, which include crumbling chromosome ends, damaged and unstable genomes and changes in the way that cells sense nutrients.

For many years, biologists have favoured the idea that these hallmarks were the result of damage such as that wrought by reactive molecules called free radicals produced by our cells鈥� metabolism. This seemed to explain why limiting the amount of food that rodents eat slows ageing and extends lifespan: the metabolic rate of food-restricted animals slows, reducing the production of free radicals. Similarly, drugs that hamper the ability of cells to sense nutrients, via a protein called mTOR that regulates metabolism, also .

Damage limitation

However, researchers have started to poke holes in this idea. For instance, manipulating the levels of free radicals in lab animals doesn鈥檛 shorten or lengthen lifespan in a way that is . Meanwhile, geneticists have made a series of startling discoveries of gene mutations that have dramatic effects on lifespan, suggesting that ageing is under genetic control. Many of these genes are involved in controlling growth, a key developmental process. 鈥淚 think ageing is a programme. It is not random wear and tear,鈥� says Wolf Reik at the Babraham Institute near Cambridge, UK.

This has prompted some researchers to revamp an idea first mooted in the 1950s 鈥� that ageing can result from the same processes that control our development. 鈥淚鈥檓 not claiming that all characteristics of ageing are caused by these developmental mechanisms going haywire,鈥� says Jo茫o Pedro de Magalh茫es at the University of Liverpool, UK. 鈥淚鈥檓 saying that there鈥檚 this notion that ageing is mostly a consequence of damage. I don鈥檛 really think it fits with all the data that鈥檚 emerging.鈥�

The idea is that developmental processes that boost an organism鈥檚 ability to survive and reproduce earlier in life keep on running, becoming pathological as time goes by. One example of this is how the lenses in our eye continue to grow throughout adulthood, resulting in long-sightedness in middle age. Another is to do with the natural pruning of connections between neurons that happens in an infant鈥檚 developing brain. suggests that the run-on of this process in late adulthood could contribute to cognitive decline. And the bone loss experienced by women after the menopause from the skeleton to support milk production in breastfeeding mothers, suggests David Gems at University College London.

Unlike the damage hypothesis, which is based on cells losing functions, the developmental hypothesis of ageing involves cells keeping functions, but deploying them inappropriately. 鈥淭hings are making sense in the most wonderful way they never did in the era of the damage maintenance paradigm,鈥� says Gems. This helps to explain why so many of the genes related to ageing are involved in things like growth, he says. It also offers a simple reason why dietary restriction, or drugs that shut down mTOR, delay ageing. Rather than reducing metabolic-related damage, these are instead putting the brakes on growth and other developmental processes by turning down the signals that drive them.

Experimental evidence to support this idea is coming in. Vadim Gladyshev and his team at Harvard Medical School, for example, , which inhibits mTOR, slowed their growth, delayed their reproductive maturity and seemed to help males in particular live longer 鈥� all consistent with there being a link between the pace of development and ageing. And suggest that turning down some growth-related genes later in life can also extend lifespan.

If ageing is linked to development, it raises the startling possibility that ageing is potentially more malleable than we once believed. If we could find ways to slow or turn off errant programmes, or even throw them into reverse gear, then this could be a route to undoing some aspects of ageing.

This isn鈥檛 as far-fetched as it sounds. At least one animal can do this naturally: the so-called immortal jellyfish, which can revert back to an earlier stage of development, seemingly becoming younger in the process (see 鈥�Secrets of the immortal jellyfish鈥�). And during the earliest stages of development, the human embryo, conceived from the cells of much older parents, reverses cellular signs of ageing and starts its life freshly rejuvenated.

Harnessing this power later in life is fast becoming a key focus of ageing research. There is, however, no way we can reverse our entire bodies backwards from adult to infant (and lots of reasons why we wouldn鈥檛 want to). But what scientists have been able to do is reverse one aspect of development: the process by which immature embryonic cells acquire their specialised adult functions. By doing so, they have also reset their biological age.

Resetting the clock

In 2006, Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University in Japan discovered that if four proteins 鈥� now known as Yamanaka factors 鈥� that are usually only active in early embryos are added into adult cells, this . Back in an embryonic-like state, they can again form any kind of cell in the body, similar to how the immortal jellyfish reverts to an earlier stage in its development. Horvath has found that these 鈥減luripotent鈥� cells have another intriguing property. When he applied a measure of ageing, known as an epigenetic clock, to them, he found that the clock had reset itself to zero.

Epigenetic clocks rely on a chemical alteration that mammalian cells make to DNA, called methylation. Horvath鈥檚 team discovered that the pattern of methylation across a cell鈥檚 genome changes over time and that it matches chronological age with surprising precision.

快猫短视频s are still trying to understand what controls these clocks and whether they are a cause or a consequence of ageing. But several clues point to development being involved. In an embryo, cells make a series of decisions about what kind of cell they are going to be. They do this by selectively switching on or off sets of genes 鈥� a process that is controlled by the proteins that package DNA, or by altering the DNA itself via methylation. Methylation marks tend to stay put, allowing cells to 鈥渞emember鈥� what genes should be active.

Many age-related methylation marks are associated with developmental genes, and the rate at which the clocks 鈥渢ick鈥� varies. It is fastest during development and runs more slowly during adulthood 鈥� a feature common to all mammals. 鈥淭his does point towards the role of developmental mechanisms driving ageing,鈥� says de Magalh茫es. If taking cells back to a pluripotent state also resets their epigenetic clock, it raises the tantalising possibility that undoing cell specialisation could somehow also undo aspects of cellular ageing.

But there is a snag. When cells are reprogrammed and lose their specialised functions, they often turn cancerous. This is switching on Yamanaka factors in mice. By tweaking the dose of factors, however, they managed to . Then, in 2020, a team led by David Sinclair at Harvard Medical School , improving their age-related loss of vision and demonstrating the feasibility of rejuvenating cells without fully reprogramming them.

A flurry of recent findings are backing this up. For example, Reik and his colleague Diljeet Gill at the Babraham Institute have discovered that rejuvenation takes place early on in the reprogramming process, before cell specialisation is irretrievably lost. Working with connective tissue cells called fibroblasts taken from middle-aged adults, they gave the cells a two-week pulse of Yamanaka factors and showed earlier this month that this clocks by about 30 years.

The cells temporarily 鈥渇orgot鈥� what they were, turning on some pluripotency genes and turning off some of their fibroblast genes. Then, after four weeks, they returned to their usual state, albeit epigenetically younger. 鈥淭hey do somehow remember their original cell type,鈥� says Gill. And that wasn鈥檛 all. Patterns of gene activity reverted to a younger type and these changes affected the cells鈥� function too: they produced youthful levels of a key connective tissue protein called collagen. When Gill and Reik scratched the layer of cells in the dish 鈥� effectively creating a wound 鈥� the rejuvenated cells were quicker to crawl back over the scratch and close the wound than their aged counterparts.

Groups elsewhere are reporting similar findings. Last year, a team led by Jacob Kimmel at Calico, a biotechnology firm in California aiming to develop interventions to extend lifespan, also managed to adult cells without fully reprogramming them, this time by using subsets of Yamanaka factors. And , a team led by Juan Carlos Izpisua Belmonte at the Salk Institute in California and Altos Labs, a biotech company focusing on cellular rejuvenation, used genetic engineering to switch Yamanaka factors on and off at will in healthy, aged mice and reported seeing epigenetic rejuvenation in certain tissues.

Other researchers have managed to produce epigenetic rejuvenation in rodents via the rather macabre method of of old mice with those of young ones and, in Horvath鈥檚 case, by also using blood plasma injections.

How the young blood has this effect is still to be fully elucidated, but, like reprogramming, it involves changes in the pattern of methylation seen at specific sites across the genome. It is also accompanied by alterations in gene activity to a more youthful state and, most convincingly in terms of an anti-ageing perspective, a boost in physical function such as improved muscle strength and bone repair.

For now, there are still many questions about the true meaning of epigenetic rejuvenation. Likewise, what is happening in cells with rewound clocks is unclear. But whatever is going on in these reprogramming and young blood experiments, it isn鈥檛 a complete reversal of all ageing. Gill and Reik, for example, found that the shortened chromosome ends 鈥� a hallmark of ageing 鈥� weren鈥檛 restored in their rejuvenated cells.

It is early days in our attempts to manipulate ageing, but one thing is clear: ageing is a complex process involving many factors and we should be wary of thinking in terms of . It is likely that other factors, including damage, also have their part to play in making us age.

But it does seem that human ageing is more malleable than we once supposed. A plethora of biotech companies have now sprung up, aiming to use this flexibility to forge new approaches to preventing or treating the declines of old age, such as age-related muscle loss, neurodegeneration and osteoarthritis.

In the short term, Gill envisages rejuvenating skin cells from someone and then transplanting them back to treat conditions such as wounds, burns and ulcers, without the risk of tissue rejection. And if we can work out how errant developmental programmes drive ageing, the implication is that we could find ways of turning them off without causing problems elsewhere. 鈥淚 think there are prospects where you can intervene in developmental mechanisms of ageing in a way that there isn鈥檛 a cost,鈥� says Gems, although he cautions that, at present, there is no clear evidence of overall plasticity in human ageing that could be tapped into easily. 鈥淚 think what鈥檚 exciting is the prospect of actually understanding the biology of ageing. Then, who knows what will be possible.鈥�

Longer term, and much more speculatively, de Magalh茫es wonders whether the technology might be used to rejuvenate whole organisms, including humans. 鈥淚 think it鈥檚 one of the most exciting questions in the field.鈥�