We continue to explore the causes of aging in the body, known as the hallmarks of aging, and how humanity can already influence them today in an attempt to achieve rejuvenation. Earlier, we looked at the general concept of the hallmarks of aging, as well as what can already be done about aging-related causes connected with DNA damage, telomere shortening, and epigenetic alterations, and loss of protein quality control, mitochondrial dysfunction, and cellular senescence.
This article looks at how intracellular clearance of harmful substances can become impaired, how metabolism can be disrupted, and what happens when the body’s own stem cells are no longer sufficient. And we will also explore whether it is truly possible to print functioning organs using a 3D printer.
Impaired autophagy: when the cell stops getting rid of dangerous substances
Autophagy is the cell’s built-in recycling mechanism: damaged proteins and organelles are broken down so their components can be reused. This helps cells survive stress and nutrient deficiency.
With aging, the efficiency of this process declines, damage accumulates in cells, inflammation increases, and vulnerability to neurodegeneration and metabolic dysfunction grows.
Moderate activation of autophagy (for example, using the compound spermidine) in studies prolonged the lifespan of mice and protected the cardiovascular system in old animals.
In 2024, it was shown that fasting increases spermidine levels in different species—from yeast to humans; this pathway turned out to be important for autophagy activation and for lifespan-related effects in model organisms.
Dysregulation of nutrient sensing: when the cell becomes worse at “sensing” energy availability
The body has a nutrient-sensing system — a network of signaling pathways that allows cells to detect whether energy is abundant and to decide whether conditions favor growth and reproduction or conservation and repair. Many different players are involved in this complex process (for example, insulin/IGF-1 signaling, the mTOR complex, and others), and their functionality becomes disrupted over time.
A 2009 study showed that rapamycin (an inhibitor of mTOR, one of the central nodes of nutrient sensing) significantly increased both median and maximal lifespan in genetically heterogeneous mice even when treatment began late in life.
In humans, it is almost impossible to directly assess lifespan extension in clinical trials, because waiting for such results takes too long. Therefore, researchers look at surrogate indicators: immune response, metabolic risks, and morbidity. In a study of elderly volunteers, low-dose mTOR inhibition improved the response to influenza vaccination by about 20% with relatively acceptable tolerability.
In a later study, influencing nutrient sensing was reported to reduce infection frequency and improve immune markers in older adults.
Particular attention should be paid to the well-known antidiabetic drug metformin. In a number of mouse studies, it not only improved metabolic health but also increased lifespan, by as much as nearly 38%. However, overall, the data on metformin are heterogeneous, and studies investigating its potential to delay age-associated diseases in humans are still ongoing.
Stem cell exhaustion and the possibilities of creating new organs
Many organs contain reserves of tissue stem cells and progenitor cells that help maintain tissues and repair them after damage. With age, these cells are affected by several factors at once: internal ones (DNA damage, epigenetic shifts, mitochondrial dysfunction, metabolic stress) and external ones (inflammatory signals, deterioration of the cellular niche, and failures in intercellular communication). As a result, stem cells become fewer in number, and their ability to divide and differentiate into the required cell types declines.
However, several decades ago it became possible to reprogram ordinary cells, such as skin cells, into induced pluripotent stem cells (iPSCs) and grow functional cells of other tissues from them, such as neurons. This is achieved through the action of OSKM factors (the Yamanaka factors). Thus, in a 2016 experiment, cyclic short-term expression of OSKM factors in mice with premature aging improved a number of aging features and extended lifespan.
In 2020, it was shown that expression of part of the OSK factors in mouse retinal cells can restore a more “youthful” epigenetic profile and reverse vision loss in a glaucoma model and in old mice.
However, it is possible not only to attempt to rejuvenate cells into stem cells within the body itself, but also to transplant stem cells from outside into the necessary locations.
For example, in 2015, the drug Holoclar was approved for use in the European Union; it consists of stem cells taken from the patient themself to restore the corneal surface after burns.
Stem cell transplantation is also beginning to be explored as a treatment for Parkinson’s disease—one of the most common neurodegenerative disorders associated with aging. In Parkinson’s disease, neurons that produce dopamine gradually die. As a result, the normal transmission of necessary signals is disrupted, leading to characteristic motor symptoms—tremor, rigidity, and slowness of movement.
Last year, the results of clinical trials were published, in which patients with Parkinson’s disease received transplants of dopamine neuron progenitor cells derived from iPSCs. Two years after transplantation, no serious adverse events were found in the patients, while dopamine synthesis increased by an average of 44.7%. At the same time, 4 out of 6 patients showed improvement in motor symptoms during periods when the effect of antiparkinsonian drugs was wearing off or had not yet begun, and 5 out of 6 also improved during periods when standard therapy was already active. This provides a cautious but important signal: the transplanted iPSC-derived progenitors not only survived but likely also began to function.
Similar stem-cell-based approaches are also already being used to restore heart tissue. Normally, the heart regenerates poorly, and simple “cell injection” often results in weak engraftment. Therefore, the field has shifted toward tissue patches made from heart cells (cardiomyocytes).
In three clinical cases of transplantation of a patch made of lab-grown cardiomyocytes into patients with ischemic cardiomyopathy (weakening of the heart muscle due to poor blood supply), no serious side effects related to the transplanted cells were identified over one year of observation. In all patients, symptoms of heart failure decreased, and in two of the three, left ventricular function and blood flow in the heart muscle also improved.
In addition, bioprinters are being developed that are capable of printing living tissue constructs from cells and biomaterials. So far, the most successful results have been achieved with relatively simple structures—for example, cartilage, skin, and some tissue implants. For example, the bioprinted ear implant AuriNovo became one of the notable examples of 3D bioprinting entering early clinical trials: it is a personalized living implant for reconstruction of the outer ear in patients with congenital underdevelopment of the ear, printed using the patient’s own cartilage cells. A clinical trial for it has already been initiated.
Thus, at present, humanity is beginning to influence not only intracellular processes associated with aging, but also changes at the cellular and even organ level. Moreover, some startups claim that in the near future they will be able to print or grow functional organs such as kidneys, livers, or hearts. Who knows—perhaps we are not far from the day when everyone will be able to receive a personalized functional organ capable of improving the quality of a healthy and fulfilling life!