Maria Blasco's research group has been working on telomerase gene therapy to lengthen telomeres for some years now; they are quite enthusiastic about this approach as a means to treat aging. One can't argue with the data showing extension of mouse life span, nor the results announced today in which induced telomerase activity is shown to reverse fibrosis. We can argue about what is going on under the hood, and whether or not addressing telomere length is in fact tackling the root causes of aging. Perhaps the most important difference between the views of aging outlined in the SENS rejuvenation research proposals and the later Hallmarks of Aging is that the latter places telomere length front and center as being of importance. In the SENS view, telomere length is a secondary marker, a consequence of other forms of damage.
So how can a therapy that induces telomerase activity to lengthen telomeres, something that to my eyes doesn't address root causes of aging, produce significant impact on mouse longevity? Well, there are many proven ways to produce significant gains in mouse longevity that have nothing to do with repairing damage after the SENS model. Calorie restriction, for example, is exactly a slowing of aging, a slowdown of the accumulation of damage, and it produces a larger gain in life span than telomerase gene therapy in mice. It doesn't do that much for human life span, sadly, though it is certainly good for health.
As a general rule we should expect approaches based on manipulating the operation of metabolism to produce comparatively poor effects in humans. We should expect approaches based on repairing the root cause cell and tissue damage of aging to produce better results in humans. Judging from the data in mice obtained to date - let us say comparing senolytics to remove senescent cells, one of the root causes of aging, with telomerase gene therapy, and with calorie restriction - all of the methodologies produce results that are in the same broad ballpark in terms of life span gained, in the 20-60% range.
The next decade will settle the critical question of what a rejuvenation therapy can achieve for human life expectancy in older individuals. The data will primarily involve senolytic treatments, as those the only one ready to go into trials right now. We can then compare that data with what is known of calorie restriction in humans, which is to say little gain in life span, even while delivering measurable health benefits. But for now, the research community only has data for direct comparison in examples of what is thought to be the less effective way forward, slowing aging by the adjustment of metabolism. That data exists for calorie restriction and growth hormone receptor dysfunction only.
It is far from clear that one can lump telomase gene therapy into either the bucket holding calorie restriction (slowing aging) or the bucket holding senolytics (damage repair to reverse aging). It may need a bucket of its own, for approaches that force a reversal in a secondary or later issue in aging, while leaving the underlying damage to continue to fester. Naively, one might guess that this will be better than slowing aging, and worse than repairing root causes. But the data isn't there in humans, and the entire issue is enormously complicated by the fact that all of the methods examined to date are far less capable of extending life span for long-lived species such as our own - which may or may not be the case, or the case to the same degree, for repair-based approaches.
But let us consider what is going on in this study. The mice were given lung fibrosis via bleomycin treatment, a chemotherapeutic that causes lung inflammation. It is known that inflammation of lung tissue produces the disruption of regenerative processes that result in fibrosis, the inappropriate construction of scar-like connective tissue that degrades normal tissue function. Research of the past few years points squarely towards senescent cells and their inflammatory signaling as the primary cause of this issue. There is good evidence for the removal of senescent cells to turn back fibrosis. Toxic chemotherapeutics like bleomycin cause cells to become senescent, putting them under enough stress to trigger that irreversible state change.
In humans with lung fibrosis who exhibit shorter average telomere length, replicative senescence may be the more important source of lingering senescent cells. Senescence occurs in somatic cells when they reach the Hayflick limit, the end of a countdown in which each cell division results in shorter telomeres. Shorter average telomere length implies that stem cells are not keeping up with delivering fresh new cells with long telomeres, and this may produce all sorts of systematic changes in the function, inflammatory state, and signaling environment of a tissue.
So the question here is how telomerase induction helps this situation. The researchers believe their gene therapy vector preferentially targets lung cells, so we can probably put aside consideration of possible immune system effects, such as more energetic clearance of senescent cells. One possibility is that telomerase induction in senescent cells mutes the inflammatory, harmful signaling they produce, the senescence-associated secretory phenotype (SASP). Another possibility is that it pushes senescent cells into self-destruction, either directly, or perhaps indirectly through other changes to the overall signaling environment in the tissue, particularly the contributions made by stem cells. Past work has suggested that some of the benefits in mice given telomerase gene therapy are due to renewed, more youthful stem cell activity in tissue maintenance. Regardless, I think that, given other work on fibrosis and cellular senescence, one has to look at this with a focus on senescent cells.
Idiopathic pulmonary fibrosis is a potentially lethal disease associated with the presence of critically short telomeres, currently lacking effective treatment. Researchers have succeeded in curing this disease in mice using a gene therapy that lengthens the telomeres. Telomeres are protein structures located at the ends of each chromosome; like caps, they protect the integrity of the chromosome when the cell divides. But telomeres only fulfill their protective function if they are long enough; when they shorten too much, the damaged cells cease to divide preventing tissue regeneration. Short telomeres are associated with ageing - as age increases, cells accumulate more divisions and more telomeric shortening - and also with several diseases. Pulmonary fibrosis is one of them.
In lung fibrosis, the lung tissue develops scars that cause a progressive loss of respiratory capacity. Environmental toxins play an important role in its origin, but it is known that there must also be telomeric damage for the disease to appear. Patients with pulmonary fibrosis have short telomeres whether the disease is hereditary - it runs into the family - or not. The most likely explanation is that when the telomeres become too short, the damaged cell activates a 'repair program' that induces scar formation that leads to fibrosis.
Researchers decided to address the problem about five years ago, starting with the development of an animal model that faithfully reproduces the human disease. The most widely used model until then was to apply bleomycin into the mouse lungs to induce damage, in an attempt to reproduce the environmental insult. However, in these animals the disease goes into remission in a few weeks and there is not telomere shortening. The researchers sought after a mouse model in which the environmental damage synergized to that produced by short telomeres, that is what happens in human pulmonary fibrosis. They succeeded in 2015.
The treatment consisted of introducing the telomerase gene into the lung cells using gene therapy. The researchers first modified a virus innocuous to humans (known as vectors) so that their genetic material incorporated the telomerase gene, and then injected those vectors into the animals. The basis of this work is the hypothesis that age-associated diseases can be treated by targeting the molecular and cellular processes of ageing, specifically telomere shortening. In 2012, the researchers generated mice that not only lived longer but also showed improved health by treating them with telomerase. Their work since then has aimed to develop this therapy to specifically treat age-associated diseases and telomere syndromes.
Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII).
AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.