The Sinclair lab is driven by the belief that humanity can do better and that everyone has the right to the best medical care and maximum lifespan, no matter their gender, social status, or age. Work by our lab and others has shown that the pace of aging is not inexorable or predetermined, but rather can be slowed and even reversed by a variety of approaches. These include activating the body’s defenses against aging, deleting senescent cells, and reprogramming cells in vivo. In doing so, we can protect the body against and treat both rare and common diseases including mitochondrial diseases, type 2 diabetes, Alzheimer’s disease, cardiovascular disease, and cancer.
EXAMPLES OF PROJECTS IN THE LAB:
Is aging loss of digital or analog information? Is epigenetic noise the reason we age?
We have developed “The Relocalization of Chromatin Modifiers (RCM) Hypothesis,” which proposes that epigenetic changes due to relocalization of chromatin factors in response to DNA damage may be a chief cause of aging. This is true for yeast cells and it appears to be true for all eukaryotes. In response to a DNA break, proteins that regulate gene expression move to the break to help repair, resulting in gene expression changes. In young cells, this process is reset upon completion of DNA repair. However, not all proteins make it back to where they came from, which leads to gene expression changes and a loss of cell identity. We have developed the “ICE” mouse (for inducible changes in the epigenome), which allows us to induce DNA breaks and drive epigenetic changes that accelerate aging. Work is now centered on reversing this aging process.
我们发展了“染色质修饰剂的重新定位假说” ，该假说认为，由于 DNA 损伤引起的染色质因子的重新定位而导致的表观遗传变化可能是衰老的主要原因。对于酵母细胞来说是这样，对于所有的真核生物来说也是这样。作为对 DNA 断裂的反应，调节基因表达的蛋白质向断裂处移动以帮助修复，从而导致基因表达的改变。在年轻细胞中，这一过程在 DNA 修复完成后被重置。然而，并不是所有的蛋白质都能回到它们来的地方，这会导致基因表达的改变和细胞特性的丧失。我们已经开发出“ ICE”小鼠(用于表观基因组中可诱导的变化) ，这使我们能够诱导 DNA 断裂，并驱动加速衰老的表观遗传变化。现在的工作重点是扭转这种老化过程。
C57BL/6 Siblings: Control vs ICE at 16 months of age
C57BL/6同胞: 16个月龄对照组与 ICE 比较
Reprogramming cells to be young again
Our work has led us to the conclusion that the loss of epigenetic information is likely the root cause of aging. By analogy, if DNA is the digital information on a compact disc, then aging is due to scratches. We are searching for the polish. Our work has led us to identify reprogramming factors that we believe will enable us to reset a cell’s epigenetic status and reverse its age. We have developed human-compatible viral vectors to deliver the reprogramming genes to specific tissues or the entire body, thereby causing cells to act younger and wounds to heal faster. Our current focus is on nerve regeneration and the reversal of other symptoms of aging. We see treatments being possible for companion animals and humans to dramatically improve their health and lifespan.
我们的研究使我们得出这样的结论: 表观遗传信息的丢失可能是衰老的根本原因。通过类比，如果 DNA 是光盘上的数字信息，那么衰老就是由于划痕。我们正在找指甲油。我们的工作已经引导我们识别重新编程的因素，我们相信这些因素将使我们能够重置细胞的表观遗传状态并逆转其年龄。我们已经开发出与人类相容的病毒载体，将重编程基因传递到特定组织或整个身体，从而使细胞活动更年轻，伤口愈合更快。我们目前的重点是神经再生和其他老化症状的逆转。我们看到对伴侣动物和人类的治疗可以显著地改善他们的健康和寿命。
Can we develop drugs that slow aging?
Our work on SIRT1 led us to an exciting finding that the level of nicotinamide adenine dinucleotide (NAD+), cofactor of SIRT1, declines with age. We study the mechanisms by which the NAD+ level affects DNA repair and look for therapeutic targets to improve this process. In particular, we focus on delineating the biology of NAD+-depleting and producing enzymes as direct tools to control the NAD+ level in the cells toward increased health-span and improved physiological resilience.
我们对 SIRT1的研究使我们得到了一个令人兴奋的发现: 随着年龄的增长，SIRT1的辅助因子—- 烟酰胺腺嘌呤二核苷酸蛋白水平(NAD +)会下降。我们研究 NAD + 水平影响 DNA 修复的机制，并寻找治疗靶点来改善这一过程。特别是，我们重点描述的生物学的 NAD + 消耗和生产酶的直接工具，以控制 NAD + 水平的细胞，以增加健康跨度和改善生理弹性。
The discovery of longevity genes showed that it is possible to greatly slow the pace of aging and disease by manipulating just one central pathway. This raises the possibility that we can find small molecules that can treat multiple, seemingly unrelated diseases, with a single medicine. Our lab has been highly active in this area, starting with the discovery of sirtuin activating compounds (STACs) in 2003. Since then, potent activators have been discovered and some of these are now in clinical trials, producing positive results. We have active studies to understand how STACs work at the molecular and the physiological levels using cutting-edge enzymological and structural methodologies and mouse genetic models in which we can delete genes at any time throughout the lifespan of the animal, and in specific organs. We published, for example, that the ability of resveratrol and a STAC called SRT1720 to increase mitochondrial function, require the SIRT1 gene in vivo. We have an active program to develop novel molecules that raise NAD levels. We are testing them for their effects on aging and age-related diseases. Human clinical trials with NAD-boosting molecules are ongoing.
长寿基因的发现表明，仅仅通过控制一条中枢通路，就有可能大大减缓衰老和疾病的速度。这就提出了一种可能性，我们可以找到小分子，可以用一种药物治疗多种看似不相关的疾病。我们的实验室在这一领域非常活跃，从2003年发现 sirtuin 激活化合物(STACs)开始。从那时起，已经发现了强效的激活剂，其中一些现在正在临床试验中，产生了积极的结果。我们进行了积极的研究，利用最先进的酶学和结构学方法以及小鼠遗传模型来了解 stag 在分子和生理水平上的工作原理，在这些模型中，我们可以在整个动物寿命期间的任何时候以及在特定器官中删除基因。例如，我们发表了白藜芦醇和一种叫做 SRT1720的 STAC 增强线粒体功能的能力，需要体内的 SIRT1基因。我们有一个积极的计划，开发新的分子，提高 NAD 水平。我们正在测试它们对衰老和老年相关疾病的影响。使用 NAD-boosting 分子的人体临床试验正在进行中。
Improving Health Through NAD+ Boosting
通过 NAD + Boosting 改善健康
Understanding the role of mitochondria in aging and disease
The study of mitochondria has experienced a renaissance in recent years. A large body of evidence indicates that common aging-related diseases have a mitochondrial component. Yet, surprisingly little is known about what leads to the progressive loss of mitochondrial fitness during aging. We investigate the cellular mechanisms that could be employed to maintain the mitochondrial homeostasis and ultimately prolong health-span.
One of our research avenues led to the discovery of ongoing asynchrony between the nuclear and mitochondrial genomes during aging. Utilizing novel genetic and pharmacological approaches, we are using this knowledge to restore metabolic function in aged mice back to youthful levels. We established that mitochondrial NAD+ levels dictate cell survival, which we refer to as the “Mitochondrial Oasis Hypothesis.” Following up on this work, we have formulated an exciting hypothesis that leakage of NAD+ from mitochondria is a cause of aging and memory loss.
我们的研究途径之一，导致发现了在衰老过程中核线粒体基因组和线粒体基因组之间不断的异步性。利用新的遗传学和药理学方法，我们正在利用这一知识来恢复老年小鼠的代谢功能回到年轻的水平。我们确定，线粒体 NAD + 水平决定细胞存活，我们称之为“线粒体绿洲假说”在这项工作之后，我们提出了一个令人兴奋的假设: NAD + 从线粒体泄漏是衰老和记忆丧失的原因。
We are also interested in identifying new genes and signaling cascades in the human genome that control mitochondrial function. We are developing novel genome mining algorithms, using advanced sequencing and proteomics tools, and high-throughput screening methods to map the most complete network of mitochondrial regulators. This work will provide new insights into fundamental aspects of mitochondrial biology and how mitochondrial defects may be prevented or corrected. We are also interested in finding novel secreted factors that increase mitochondrial function and are candidates for signaling factors that have recently been implicated in the systemic control of aging in simple organisms.
我们也有兴趣在人类基因组中发现控制线粒体功能的新基因和信号级联。我们正在开发新的基因组挖掘算法，使用先进的测序和蛋白质组学工具，以及 high throughput 方法来绘制最完整的线粒体调节器网络。这项工作将为线粒体生物学的基本方面以及如何防止或纠正线粒体缺陷提供新的见解。我们也有兴趣发现新的分泌因子，增加线粒体功能和候选人的信号因子，最近有牵连的系统控制衰老的简单的生物体。
Mitochondrial network surrounding nucleus (mitoTimer)
Delaying menopause and reversing female infertility
Ovarian stem cells are a recently discovered type of cell than can give rise to oocytes in culture and produce healthy oocytes in vivo. This work may overturn the dogma that a female is born with a set number of eggs that are simply lost over time due to damage and genomic instability. We are using our knowledge gained from studying aging and metabolism to understand how female infertility may be delayed or reversed. Our goals are to identify genes and small molecules that can reactivate ovarian stem cells in vivo to treat premature ovarian failure, chemotherapeutic ovarian failure (in cancer patients) and extending the healthy and fertile period for women.
Two cell embryos
Can we slow down or even reverse neurodegenerative diseases?
Neurodegenerative diseases strike primarily in mid to late life, and thus their incidence rises in aging populations. We are actively working on identifying the molecular drivers of neuronal degeneration such as novel genes, epigenetic changes and metabolic imbalance by applying diverse experimental approaches including classical studies of genes and gene function, advanced omics and novel transgenic mouse models, including the NICE mouse (for neuronal inducible changes in the epigenome) which allows us to study the effects of epigenetic changes in the aging brain. Through our studies we aim to develop therapeutic interventions that can prevent the onset or slow the progression of disease, and possibly even reverse it by regenerating the damaged tissues.
神经退行性疾病主要发生在中晚年，因此在老年人群中发病率上升。我们正在通过应用不同的实验方法，包括经典的基因和基因功能研究、先进的基因组学和新的转基因小鼠模型，包括 NICE 小鼠(神经元诱导的表观基因组变化) ，积极研究神经元变性的分子驱动因素，如新基因、表观遗传变化和代谢失衡，这使我们能够研究表观遗传变化对衰老大脑的影响。通过我们的研究，我们的目标是开发治疗干预措施，可以预防疾病的发生或减缓疾病的进展，甚至可能通过再生受损的组织来逆转疾病。
Healthy brain vs brain with A-beta plaques – photo courtesy of Jaime Ross
健康的大脑对抗有 A-beta 斑块的大脑-图片由 Jaime Ross 提供
Uncovering the human secretome
Peptide hormones regulate embryonic development and most physiological processes by acting as endocrine or paracrine signals. They also hold great therapeutic potential either as medicines or targets for treating both common and rare diseases. Yet identifying peptide-coding genes below ~300 base pairs is inherently difficult because they exist within the “genomic noise”. Our goal is to uncover the human secretome and use newly discovered hormones to improve the human condition. Over the past few years, we have developed a unique pipeline of technologies that combines breakthroughs in math, computer hardware and software, proteomics, mass spectrometry, and high-throughput screening, each of which has been optimized and integrated. Using this platform, for which we have been awarded an NIH Director’s Pioneer Award, we have discovered thousands of putative peptide-coding genes. Our aim is to screen these peptides for activities to determine their biological roles and potential therapeutic application in biology and disease settings.
肽激素通过作为内分泌或旁分泌信号调节胚胎发育和大多数生理过程。作为治疗常见和罕见疾病的药物或目标，它们也具有巨大的治疗潜力。然而识别低于300碱基对的肽编码基因是天生的困难，因为它们存在于“基因组噪音”中。我们的目标是揭示人类的分泌器，并利用新发现的激素来改善人类的状况。在过去的几年里，我们已经开发出了一系列独特的技术，这些技术结合了数学、计算机硬件和软件、蛋白质组学、质谱法和 high throughput 等领域的突破，每一项都经过了优化和整合。利用这个平台，我们已经获得了美国国立卫生研究院院长先驱奖，我们发现了数千个假定的肽编码基因。我们的目的是筛选这些肽的活动，以确定其生物作用和潜在的治疗应用在生物学和疾病的设置。